Tofa analogs useful in treating dermatological disorders or conditions

ABSTRACT

This invention is directed to analogs of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and their use in the treatment of dermatological disorders or conditions characterized by sebaceous gland hyperactivity, such as acne and oily skin, and other dermatological disorders and conditions. This invention is also directed to pharmaceutical compositions comprising analogs of TOFA and a pharmaceutically acceptable excipient for dermatological or oral administration. Formula (I)

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Patent Application No. 61/224,042, filed Jul. 8, 2009, whichis incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention is directed to the use of analogs of5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) for the treatment ofdermatological disorders or conditions characterized by sebaceous glandhyperactivity, such as acne and oily skin. This invention is alsodirected to pharmaceutical and dermatological compositions comprisinganalogs of TOFA for use in treating dermatological disorders orconditions characterized by sebaceous gland hyperactivity, such as acneand oily skin.

BACKGROUND OF THE INVENTION

Hyperactive sebaceous gland disorders, such as acne vulgaris (acne), arecommon dermatological conditions affecting many people. Acne typicallypresents at the onset of puberty and peaks in incidence between 14 and19 years of age. The prevalence of acne is greatly reduced by the middleof the third decade of life. Acne pathogenesis is multi-factorialinvolving sebaceous gland hyperactivity (increased production of sebum)with seborrhea, abnormal keratinocyte proliferation/desquamation andbacterial colonization promoting local inflammatory changes. As aconsequence of the surge in androgen production at puberty, increasedsebum production occurs along with abnormal desquamation of theepithelial lining of hair follicles. This mixture of sebum and celldebris is the basic ingredient of the comedone providing an idealenvironment for the growth of Propionibacterium acnes (P. acnes), ananaerobic gram-positive bacterium that is part of normal skin flora anda key contributor to inflammatory acne. Bacterial-derived chemotacticfactors and pro-inflammatory mediators subsequently foster localinflammatory reactions.

The clinical presentation of acne ranges from open comedones(whiteheads) and closed comedones (blackheads) for mild acne to thepapules, pustules, nodules and cystic or mixed lesions for severe,inflammatory acne. Acne lesions typically occur on the face, upper back,chest and upper arms. The clinical course of acne tends to wax and wane.The severity of the condition is affected by multiple factors includingseasonal and psychological influences as well as self-induced trauma bypatients who habitually manipulate their lesions. Although generallytransitory in course, moderate to severe inflammatory acne presents atrue disease state that may cause long-term consequences for the subjectincluding, but not limited to, socially disabling psychological damageand disfiguring physical scars.

A wide array of therapies for treating from moderate to severe acne isavailable. These therapies may affect specific aspects of the conditionor in some cases affect several pathogenic factors. However, there aresignificant deficiencies in the currently available therapies for acne.Dermatological therapies are not fully effective against mild tomoderate acne and many of the agents employed in these therapies produceskin irritation. Therapies employing dermatological retinoids andbenzoyl peroxide are effective against mild to moderate acne by removingcomedones, killing bacteria and/or reducing inflammation. Therapiesemploying antibiotics, given either dermatologically or orally, may beused to treat mild to moderate acne through the antibiotics'bacteriostatic and anti-inflammatory activities. Oral antibiotics do nottypically produce satisfactory lesion clearance. In general, oralantibiotics used in the treatment of acne are slow-acting and require atreatment period of 3-6 months for optimum results. Hence compliance maybe difficult, especially among younger patients. Long-term use ofantibiotics is also associated with the spectre of bacterialantibiotic-resistance. Light-based therapies, such as 420-nm blue lightor 1450-nm thermal lasers, can be used to treat mild to moderate acnebased on their respective anti-bacterial photodynamic or thermal effecton sebaceous glands.

With current guidelines, the treatment regimen of choice for individualswith moderate to severe acne is oral antibiotics in combination with adermatological agent such as a retinoid. For patients with recalcitrantnodular acne, first line therapy may consist of an oral retinoid, suchas Accutane® (13-cis-retinoic acid). Accutane® has a strong inhibitoryaction on sebaceous glands and is therefore useful in removingcomedones, reducing inflammation and inhibiting proliferation,differentiation and lipogenesis within sebaceous glands. In addition,Accutane® is also used to treat moderate or severe acne in patients atrisk of physical or psychological scarring. Accutane® has long historyof proven efficacy in treating acne. The majority of individuals treatedwith Accutane® experience remission with 3-6 months of daily dosing. Insome cases, the treatment produces long-lasting benefit and ispotentially curative. On the other hand, Accutane® is a recognizedteratogen and is known to produce significant systemic adverse effectsincluding elevated risk of mental depression, increased blood lipidlevels and deleterious mucocutaneous changes. The strong inhibitoryaction of Accutane® on sebaceous gland activity clearly distinguishes itfrom the effects of dermatological retinoids and dermatological/oralantibiotics. However, topical treatment of acne is still preferred sincethis approach minimizes the risk of deleterious systemic effectsassociated with Accutane®. Drugs like Accutane®, which are effectiveorally, may have substantially less activity when administeredtopically, potentially due to their limited penetration into the skinand/or sebaceous glands.

Reducing sebum production as a means to treat acne has also beendescribed. See, e.g., Zouboulis, C. C. et al., “Zileuton, an oral5-lipoxygenase inhibitor, directly reduces sebum production”,Dermatology (2005), Vol. 210, pp. 36-38; and Zouboulis, C. C. et al., “Anew concept for acne therapy: a pilot study with zileuton, an oral5-lipoxygenase inhibitor”, Arch. Dermatol. (2003), Vol. 139, pp.668-670. Zileuton, an orally active inhibitor of 5-lipoxygenase, theenzyme that catalyzes the formation of leukotriene B4 (LTB4) fromarachidonic acid, was tested on moderate to severe acne patients. LTB4promotes production of sebum lipids. The results of this study revealeda 65% reduction of sebum lipids and a 71% reduction in inflammatorylesions at 12 weeks. This work indicated that acne could significantlyimprove with a non-retinoid that acts by inhibiting sebum production.

There exists a need, therefore, for a fast-acting, effective and safedermatological or oral therapy for acne and other dermatologicaldisorders which are characterized by sebaceous gland hyperactivity.

SUMMARY OF THE INVENTION

Described herein are analogs of 5-(tetradecyloxy)-2-furancarboxylic acid(TOFA) and methods for using the analogs for the treatment ofdermatological disorders or conditions characterized by sebaceous glandhyperactivity, such as acne vulgaris, acne conglobata, choracne,rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis,sebaceous gland hyperplasia, Meibomian gland dysfunction of facialrosacea, mitogenic alopecia, and oily skin.

Accordingly, in one aspect, this invention is directed to compounds offormula

wherein:

-   R¹ is —O—R², —O—R³—OR², —O—R³—OC(O)—N(R⁵)R⁶, —O—R³—N(R⁵)R⁶,    —O—R³—N(R⁴)C(O)OR⁵, —O—R³—C(O)OR⁵, —O—R³—C(O)N(R⁵)R⁶ or    —N(R⁵)S(O)₂—R⁴;-   each R² is independently alkyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted substituted    heteroarylalkyl;-   each R³ is independently an optionally substituted alkylene chain;    and-   R⁴ is optionally substituted alkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   each R⁵ is independently hydrogen, alkyl, optionally substituted    cycloalkyl, optionally substituted aryl or optionally substituted    aralkyl; and-   each R⁶ is alkyl, optionally substituted cycloalkyl, optionally    substituted aralkyl or —R³—C(O)OR⁴;-   or any R⁵ and R⁶, together with the nitrogen to which they are both    attached, form an optionally substituted N-heterocyclyl or an    optionally substituted N-heteroaryl;-   as a single stereoisomer or as a mixture thereof;-   or a pharmaceutically acceptable salt thereof.

Another aspect of this invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I), as set forth above, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.

In another aspect, this invention is directed to a method of treating ahuman having a dermatological disorder or condition characterized bysebaceous gland hyperactivity, wherein the method comprisesadministering to the human in need thereof a therapeutically effectiveamount of a compound of formula (I), as set forth above, or apharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to a method of treating ahuman having a dermatological disorder or condition characterized bysebaceous gland hyperactivity, wherein the method comprisesadministering to the human in need thereof a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I), as set forth above, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Another aspect of this invention is directed to a method of inhibitingsebaceous gland activity in a human, wherein the method comprisesadministering to the human in need thereof a therapeutically effectiveamount of a compound of formula (I), as set forth above, or apharmaceutically acceptable salt thereof.

Another aspect of this invention is directed to a method of inhibitingsebaceous gland activity in a human, wherein the method comprisesadministering to the human in need thereof a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I), as set forth above, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Another aspect of this invention is directed to a method of treating ahuman having a disorder or condition characterized by inflammation,wherein the method comprises administering to the human in need thereofa pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I), as set forth above, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

Another aspect of this invention is directed to a method of reducing Tcell proliferation and cytokine secretion in a human having a disorderor condition characterized by inflammation, the method comprisingadministering to the human in need thereof a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I), as set forth above, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Of the various aspects of the invention set forth above, it isunderstood that the compounds of formula (I) do not encompass compoundsspecifically disclosed or claimed in the following U.S. patents, theentire disclosures of which are incorporated in full by referenceherein: U.S. Pat. No. 4,110,351; U.S. Pat. No. 4,146,623; U.S. Pat. No.4,602,099; and U.S. Pat. No. 4,980,371. In a particular embodiment, thecompounds of Formula (I) excludes 5-dodecyloxy-2-furoic acid,5-tetradecyloxy-2-furoic acid methyl ester, 5-tetradecyloxy-2-furoicacid piperidinoethyl ester, and 5-tetradecyloxy-2-furoic acid3-pyrrolidinyl ester.

The above aspects of the invention and embodiments thereof are describedin more detail below.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 provides the results of an in vivo assay to evaluate the effectof topical application of TOFA in parallel with three compounds of theinvention on hamster ear sebaceous glands. Mean sebaceous gland countswith standard deviations (5 animals per group) for untreated and treatedears are shown. *P<0.05 by Students Test.

FIG. 2 shows the result of a further in vivo assay to assess hamstersebaceous gland size after 21 days of application of Compound A as wellas one and two weeks following cessation of treatment. Mean sebaceousgland counts with standard deviations (7-8 animals per group at eachtime point) for untreated and treated ears are shown. *P<0.05; **P<0.005as compared to solvent-treated animals.

FIG. 3 shows the histological appearance of ear cross-sections preparedin a study in which animals were treated for 21 consecutive days withcontrol vehicle (40% DMA/30% acetone/30% ethanol), TOFA and Compound A,respectively.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

In addition to the foregoing, as used in the specification and appendedclaims, unless specified to the contrary, the following terms have themeaning indicated:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Trifluoromethyl” refers to the —CF₃ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms, and which is attached tothe rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted by one of the following groups:alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶,—N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —S(O)_(t)OR¹⁶(where t is 1 to 2), —S(O)_(p)R¹⁶ (where p is 0 to 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR¹⁶ is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single bond and to the radical groupthrough a single bond. The points of attachment of the alkylene chain tothe rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwisespecifically in the specification, an alkylene chain may be optionallysubstituted by one of the following groups: alkyl, alkenyl, halo,haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl,oxo, trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴,—C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁶, —N(R¹⁴)C(O)R¹⁶, —N(R¹⁴)S(O)_(t)R¹⁶ (wheret is 1 to 2), —S(O)_(t)OR¹⁶ (where t is 1 to 2), —S(O)_(p)R¹⁶ (where pis 0 to 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may included fused orbridged ring systems. Aryl radicals include, but are not limited to,aryl radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, the term “aryl” orthe prefix “ar-” (such as in “aralkyl”) is meant to include arylradicals optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, alkenyl,halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, heteroaryl,heteroarylalkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴,—R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2),—R¹⁵—N═C(OR¹⁴)R¹⁴, —R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2),—R¹⁵—S(O)_(p)R¹⁶ (where p is 0 to 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where tis 1 to 2) where each R¹⁴ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵ isindependently a direct bond or a straight or branched alkylene oralkenylene chain; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. The alkylene chain part of the aralkyl radical may be optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical may be optionally substituted as described above foran aryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, and the like. Unless otherwise stated specificallyin the specification, the term “cycloalkyl” is meant to includecycloalkyl radicals which are optionally substituted by one or moresubstituents independently selected from the group consisting of alkyl,alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂,—R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2),—R¹⁵—N═C(OR¹⁴)R¹⁴, —R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2),—R¹⁵—S(O)_(p)R¹⁶ (where p is 0 to 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where tis 1 to 2) where each R¹⁴ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵ isindependently a direct bond or a straight or branched alkylene oralkenylene chain; and each R¹⁶ is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of two to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxo-1,3-dioxol-4yl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above which are optionally substituted by one ormore substituents selected from the group consisting of alkyl, alkenyl,halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂,—R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶,—R¹⁵—N(R¹⁴)C(O)R¹⁶, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2),—R¹⁵—N═C(OR¹⁴)R¹⁴, —R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2),—R¹⁵—S(O)_(p)R¹⁶ (where p is 0 to 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where tis 1 to 2) where each R¹⁴ is independently hydrogen, alkyl, alkenyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R¹⁵ isindependently a direct bond or a straight or branched alkylene oralkenylene chain; and each R¹⁶ is alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical maybe optionally substituted as described above for heterocyclyl radicals.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkylene chain at the nitrogen atom. The alkylene chain of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl group.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, the term “heteroaryl” is meant toinclude heteroaryl radicals as defined above which are optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl,cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R¹⁵—OR¹⁴,—R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁶, —R¹⁵—N(R¹⁴)C(O)R¹⁶,—R¹⁵—N(R¹⁴)S(O)_(t)R¹⁶ (where t is 1 to 2), —R¹⁵—N═C(OR¹⁴)R¹⁴,—R¹⁵—S(O)_(t)OR¹⁶ (where t is 1 to 2), —R¹⁵—S(O)_(p)R¹⁶ (where p is 0 to2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 to 2) where each R¹⁴ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R¹⁵ is independently a direct bondor a straight or branched alkylene or alkenylene chain; and each R¹⁶ isalkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical may beoptionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkylradical may be optionally substituted as defined above for a heteroarylgroup. The alkylene chain part of the heteroarylalkyl radical may beoptionally substituted as defined above for an alkylene chain.

“Dermatological disorder or conditions” includes disorders involvinghyperactive sebaceous gland activity including, for example, acnevulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea,seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomiangland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.

“Dermatologically acceptable excipient” includes without limitation anyadjuvant, carrier, vehicle, excipient, glidant, sweetening agent,diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier, including those approved by the UnitedStates Food and Drug Administration as being acceptable fordermatological use on humans or domestic animals, or which are known, orare suitable for use in dermatological compositions.

As is known, the skin (especially stratum corneum) provides a physicalbarrier to the harmful effects of the external environment. In doing so,it also interferes with the absorption or transdermal delivery oftopical therapeutic drugs. Thus, a suitable dermatologically acceptableexcipient may include one or more penetration enhancers (or permeationenhancers), which are substances that promote the diffusion of thetherapeutic drugs (e.g., the TOFA analogs described herein) through theskin barrier. They typically act to reduce the impedance or resistanceof the skin to allow improved permeation of the therapeutic drugs. Inparticular, substances which would perturb the normal structure of thestratum corneum are capable of disrupting the intercellular lipidorganization, thus reducing its effectiveness as a barrier. Thesesubstances could include any lipid material which would partition intothe stratum corneum lipids causing a direct effect or any material whichwould effect the proteins and cause an indirect perturbation of thelipid structure. Furthermore, solvents, such as ethanol, can removelipids from the stratum corneum, thus destroying its lipid organizationand disrupting its barrier function.

Examples of penetration enhancers or barrier function disruptersinclude, but are not limited to, alcohol-based enhancers, such asalkanols with one to sixteen carbons, benzyl alcohol, butylene glycol,diethylene glycol, glycofurol, glycerides, glycerin, glycerol, phenethylalcohol, polypropylene glycol, polyvinyl alcohol, and phenol;amide-based enhancers, such as N-butyl-N-dodecylacetamide, crotamiton,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl formamide, andurea; amino acids, such as L-α-amino acids and water soluble proteins;azone and azone-like compounds, such as azacycloalkanes; essential oils,such as almond oil, amyl butyrate, apricot kernel oil, avocado oil,camphor, castor oil, 1-carvone, coconut oil, corn oil, cotton seed oil,eugenol, menthol, oil of anise, oil of clove, orange oil, peanut oil,peppermint oil, rose oil, safflower oil, sesame oil, shark liver oil(squalene), soybean oil, sunflower oil, and walnut oil; vitamins andherbs, such as aloe, allantoin, black walnut extract, chamomile extract,panthenol, papain, tocopherol, and vitamin A palmitate; waxes, such ascandelilla wax, carnuba wax, ceresin wax, beeswax, lanolin wax, jojobaoil, petrolatum; mixes, such as primary esters of fractionated vegetableoil fatty acids with glycerine or propylene glycol, and interesterifiedmedium chain triglyceride oils; fatty acids and fatty acid esters, suchas amyl caproate, butyl acetate, caprylic acid, cetyl ester, diethylsebacate, dioctyl malate, elaidic acid ethyl caprylate, ethyl glycolpalmitostearate, glyceryl beheate, glucose glutamate, isobutyl acetate,laureth-4, lauric acid, malic acid, methyl caprate, mineral oil,myristic acid, oleic acid, palmitic acid, PEG fatty esters, polyoxylenesorbitan monooleate, polypropylene glycols, propylene glycols,saccharose disterate, salicylic acid, sodium citrate, stearic acid,soaps, and caproic-, caprylic-, capric-, and lauric-triglycerides;macrocylics, such as butylated hydroxyanisole, cyclopentadecanolide,cyclodextrins; phospholipid and phosphate enhancers, such asdialkylphosphates, ditetradecyl phosphate, lecithin, 2-pyrrolidonederivatives, such as alkyl pyrrolidone-5-carboxylate esters,pyroglutamic acid esters, N-methyl pyrrolidone, biodegradable softpenetration enhancers, such as dioxane derivatives and dioxolanederivatives; sulphoxide enhancers, such as dimethyl sulphoxide anddecylmethyl sulphoxide; acid enhancers, such as alginic acid, sorbicacid, and succinic acid; cyclic amines; imidazolinones; imidazoles;ketones, such as acetone, dimethicone, methyl ethyl ketone, andpentanedione; lanolin derivatives, such as lanolin alcohol, PEG 16lanolin, and acetylated lanolin; oxazolines; oxazolindinones; prolineesters; pyrroles, urethanes; and surfactants, such as nonoxynols,polysorbates, polyoxylene alcohols, polyoxylene fatty acid esters,sodium lauryl sulfate, and sorbitan monostearate.

“Dermatologically effective amount” refers to that amount of an activeingredient which, when administered dermatologically (i.e., systemicallyor locally, including, for example, topically, intradermally,intravenously, orally or by use of an implant, that affordadministration to the sebaceous glands) to a human, is sufficient toeffect the desired treatment, as defined below, of the disorder orcondition of interest in the human. The amount of an active ingredientwhich constitutes a “dermatologically effective amount” will varydepending on the active ingredient, the disorder or condition and itsseverity, and the age of the human to be treated, but can be determinedroutinely by one of ordinary skill in the art having regard to his ownknowledge and to this disclosure.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g. cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. When a functional group is described as “optionallysubstituted,” and in turn, substitutents on the functional group arealso “optionally substituted” and so on, for the purposes of thisinvention, such iterations are limited to five, preferably suchiterations are limited to two.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment of the disease or condition ofinterest in a mammal, preferably a human, having the disease orcondition. The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the disease or condition and its severity, the manner of administration,and the age of the mammal to be treated, but can be determined routinelyby one of ordinary skill in the art having regard to his own knowledgeand to this disclosure. Preferably, for purposes of this invention, a“therapeutically effective amount” is that amount of a compound ofinvention which is sufficient to inhibit sebaceous gland activity.

“Treating” or “treatment”, as used herein, covers the treatment of thedisease or condition of interest in a mammal, preferably a human, andincludes:

(i) preventing the disease or condition from occurring in the mammal;

(ii) inhibiting the disease or condition in the mammal, i.e., arrestingits development;

(iii) relieving the disease or condition in the mammal, i.e., causingregression of the disease or condition; or

(iv) relieving the symptoms of the disease or condition in the mammal,i.e., relieving the symptoms without addressing the underlying diseaseor condition; or

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallisation. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ChemDrawVersion 10 software naming program (CambridgeSoft). For complex chemicalnames employed herein, a substituent group is named before the group towhich it attaches. For example, 2 cyclopropylethyl comprises an ethylbackbone with cyclopropyl substituent. In chemical structure diagrams,all bonds are identified, except for some carbon atoms, which areassumed to be bonded to sufficient hydrogen atoms to complete thevalency.

The use of parentheses in substituent groups is used herein to conservespace. Accordingly, the use of parenthesis in a substituent groupindicates that the group enclosed within the parentheses is attacheddirectly to the atom preceding the parenthesis. For example, one of thechoices for R¹ is the —O—R³—OC(O)—N(R⁵)R⁶ group. The formula for thisgroup can be drawn as follows:

Thus, for example, a compound of formula (I) wherein R¹3-morpholinopropoxy; i.e., a compound of the following formula:

is named herein as 3-morpholinopropyl5-(tetradecyloxy)furan-2-carboxylate.

Embodiments of the Invention

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments are preferred.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, one embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R²; and-   R² is independently alkyl or heterocyclylalkyl.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   isopropyl 5-(tetradecyloxy)furan-2-carboxylate;-   4-methylpentyl 5-(tetradecyloxy)furan-2-carboxylate; and-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    5-(tetradecyloxy)furan-2-carboxylate.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R²; and-   R² is haloalkyl or substituted aryl.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2-carboxylate;-   2,2,2-trichloroethyl 5-(tetradecyloxy)furan-2-carboxylate;-   2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate; and-   2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R³—OR²;-   R² is optionally substituted heterocyclylalkyl; and-   R³ is an optionally substituted alkylene chain.

Of this embodiment, one embodiment is a compound of formula (I) which is3-(tetrahydro-2H-pyran-2-yloxy)propyl5-(tetradecyloxy)furan-2-carboxylate.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R³—OC(O)—N(R⁵)R⁶;-   each R² is independently alkyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted substituted    heteroarylalkyl;-   R³ is an optionally substituted alkylene chain; and-   R⁵ is hydrogen, alkyl, optionally substituted cycloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁶ is alkyl, optionally substituted cycloalkyl, optionally    substituted aralkyl or —R³—C(O)OR³; and-   or any R⁵ and R⁶, together with the nitrogen to which they are both    attached, form an optionally substituted N-heterocyclyl or an    optionally substituted N-heteroaryl.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   1-(benzyl(methyl)carbamoyloxy)ethyl    5-(tetradecyloxy)furan-2-carboxylate;-   1-((2-ethoxy-2-oxoethyl)(methyl)carbamoyloxy)ethyl    5-(tetradecyloxy)furan-2-carboxylate;-   4 (2S)-2-benzyl    1-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)pyrrolidine-1,2-dicarboxylate;-   1-(4-phenylcyclohexanecarbonyloxy)ethyl    5-(tetradecyloxy)furan-2-carboxylate;-   1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl    3-phenylpyrrolidine-1-carboxylate;-   1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl    3,4-dihydroisoquinoline-2(1H)-carboxylate;-   1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl    piperidine-1-carboxylate;-   1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl    morpholine-4-carboxylate;-   1-tert-butyl    4-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)piperazine-1,4-dicarboxylate;    and-   1-(dicyclohexylcarbamoyloxy)ethyl    5-(tetradecyloxy)furan-2-carboxylate.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R³—N(R⁵)R⁶;-   R³ is an optionally substituted alkylene chain; and-   R⁵ is hydrogen, alkyl, optionally substituted cycloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁶ is alkyl, optionally substituted cycloalkyl, optionally    substituted aralkyl or —R³—C(O)OR⁴; and-   or any R⁵ and R⁶, together with the nitrogen to which they are both    attached, form an optionally substituted N-heterocyclyl or an    optionally substituted N-heteroaryl.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   2-(dimethylamino)ethyl 5-(tetradecyloxy)furan-2-carboxylate;-   2-morpholinoethyl 5-(tetradecyloxy)furan-2-carboxylate;or-   3-morpholinopropyl 5-(tetradecyloxy)furan-2-carboxylate.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R³—N(R⁴)C(O)OR⁶-   R³ is an optionally substituted alkylene chain; and-   R⁴ is optionally substituted alkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl; and-   R⁵ is hydrogen, alkyl, optionally substituted cycloalkyl, optionally    substituted aryl or optionally substituted aralkyl.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R³—C(O)OR⁵-   R³ is an optionally substituted alkylene chain; and-   R⁵ is hydrogen, alkyl, optionally substituted cycloalkyl, optionally    substituted aryl or optionally substituted aralkyl.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —O—R³—C(O)N(R⁵)R⁶;-   R³ is an optionally substituted alkylene chain; and-   R⁵ is hydrogen, alkyl, optionally substituted cycloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁶ is alkyl, optionally substituted cycloalkyl, optionally    substituted aralkyl or —R³—C(O)OR⁴;-   or R⁵ and R⁶, together with the nitrogen to which they are both    attached, form an optionally substituted N-heterocyclyl or an    optionally substituted N-heteroaryl.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   2-(benzyl(methyl)amino)-2-oxoethyl    5-(tetradecyloxy)furan-2-carboxylate;-   tert-butyl    4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine-1-carboxylate;-   2-(dicyclohexylamino)-2-oxoethyl    5-(tetradecyloxy)furan-2-carboxylate;-   2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl    5-(tetradecyloxy)furan-2-carboxylate;-   2-oxo-2-(4-phenylpiperzin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate;-   2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl    5-tetradecyloxy)furan-2-carboxylate;-   2-oxo-2-(piperidin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate;-   2-morpholino-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate;-   2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl    5-(tetradecyloxy)furan-2-carboxylate; and-   (S)-benzyl    1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate.

Of the compounds of formula (I), as set forth above in the Summary ofthe Invention, another embodiment is a compound of formula (I) wherein:

-   R¹ is —N(R⁵)S(O)₂—R⁴;-   R⁴ is optionally substituted alkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl; and-   R⁵ is independently hydrogen, alkyl, optionally substituted    cycloalkyl, optionally substituted aryl or optionally substituted    aralkyl.

Of this embodiment, one embodiment is a compound of formula (I) which is5-(tetradecyloxy)-N-tosylfuran-2-carboxamide.

Of the pharmaceutical compositions, as set forth above in the Summary ofthe Invention, one embodiment is wherein the pharmaceutical compositionis a dermatological composition comprising a dermatologically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and a dermatologically acceptable excipient.

Another embodiment is wherein the dermatological composition is a gelformulation, an alcoholic gel formulation, a hydroalcoholic gelformulation, or a cream formulation.

Another embodiment is wherein the pharmaceutical composition is an oralcomposition comprising a dermatologically effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, and apharmaceutically acceptable excipient.

Of the method of treating a human having a dermatological disorder orcondition characterized by sebaceous gland hyperactivity, as set forthabove in the Summary of the Invention, one embodiment of this method iswherein the dermatological disorder or condition is selected from thegroup consisting of acne vulgaris, acne conglobata, choracne, rosacea,Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceousgland hyperplasia, Meibomian gland dysfunction of facial rosacea,mitogenic alopecia, and oily skin.

Another embodiment of this method is wherein the dermatological disorderis acne.

Another embodiment of this method is wherein the dermatological disorderis oily skin.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered topically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered systemically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered orally.

Of the method of treating a human having a dermatological disorder orcondition characterized by sebaceous gland hyperactivity, as set forthabove in the Summary of the Invention, one embodiment of this method iswherein the dermatological disorder or condition is selected from thegroup consisting of acne vulgaris, acne conglobata, choracne, rosacea,Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceousgland hyperplasia, Meibomian gland dysfunction of facial rosacea,mitogenic alopecia, and oily skin.

Another embodiment of this method is wherein the dermatological disorderis acne.

Another embodiment is of this method wherein the dermatologicalcondition is oily skin.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered topically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered systemically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), as set forth above, or apharmaceutically acceptable salt thereof, is administered orally.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a dermatological composition and the pharmaceuticallyacceptable excipient is a dermatologically acceptable excipient.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a systemic composition.

Another embodiment of this method is wherein the pharmaceuticalcomposition is an oral composition.

Of the method of inhibiting sebaceous gland activity in a human, whereinthe method comprises administering to the human in need thereof atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, as set forth above in theSummary of the Invention, one embodiment of this method is wherein thetherapeutically effective amount is administered topically.

Another embodiment of this method is wherein the therapeuticallyeffective amount is administered systemically.

Another embodiment of this method is wherein the therapeuticallyeffective amount is administered orally.

Of the method of inhibiting sebaceous gland activity in a human, whereinthe method comprises administering to the human in need thereof apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient, as set forth abovein the Summary of the Invention, one embodiment of this method iswherein the therapeutically effective amount of a compound of formula(I), as set forth above, or a pharmaceutically acceptable salt thereof,is administered topically.

Another embodiment of this method is wherein the pharmaceuticalcomposition is administered systemically.

Another embodiment of this method is wherein the pharmaceuticalcomposition is administered orally.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a dermatological composition and the pharmaceuticallyacceptable excipient is a dermatologically acceptable excipient.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a systemic composition.

Another embodiment of this method is wherein the pharmaceuticalcomposition is an oral composition.

Of the method of treating a human having a disorder or conditioncharacterized by inflammation, as set forth above in the Summary of theInvention, one embodiment of this method is wherein the disorder orcondition is inflammatory acne.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered topically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered systemically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered orally.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a dermatological composition and the pharmaceuticallyacceptable excipient is a dermatologically acceptable excipient.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a systemic composition.

Another embodiment of this method is wherein the pharmaceuticalcomposition is an oral composition.

Of the method of reducing T cell proliferation and cytokine secretion ina human having a disorder or condition characterized by inflammation, asset forth above in the Summary of the Invention, one embodiment of thismethod is wherein the disorder or condition is inflammatory acne.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered topically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered systemically.

Another embodiment of this method is wherein the therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, is administered orally.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a dermatological composition and the pharmaceuticallyacceptable excipient is a dermatologically acceptable excipient.

Another embodiment of this method is wherein the pharmaceuticalcomposition is a systemic composition.

Another embodiment of this method is wherein the pharmaceuticalcomposition is an oral composition.

Utility of the Invention

Increased sebum production due to sebaceous gland hyperactivity is oneof several factors generally believed to be contributors to acnepathogenesis. In the formation of sebum, there is stepwisedifferentiation of sebocytes, a specialized epithelial cell type,arising from basal progenitor cells leading to lipid-forming cells whichas they progress toward the gland outlet. These enlarged cellsultimately rupture (holocrine secretion) releasing their lipid-richcontent (sebum). The overall makeup of sebum consists of squalene (12%),cholesterol (2%), wax esters (26%), and diglycerides/triglycerides/freefatty acids (57%) (see, Zouboulis et al., “An oral 5-lipoxygenaseinhibitor, directly reduces sebum production”. Dermatology. (2005)210:36-38). Free fatty acid levels may be increased by bacterialdegradation of the di- and triglycerides present within sebum (see,Thiboutot D. “Regulation of human sebaceous glands” J. Invest Dermatol.(2004) 123:1-12).

Free fatty acids may also promote the inflammatory aspects of acne byactivating local immune cells and their release of a variety ofpro-inflammatory factors.

Fatty acid synthesis starts with the carboxylation of acetyl CoA tomalonyl CoA. This irreversible reaction is the committed step in fattyacid synthesis. The synthesis of malonyl CoA is catalyzed by acetyl CoAcarboxylase (ACC) (See, Brownsey, R. W. et al., “Regulation ofacetyl-CoA carboxylase”, Biochem Soc. Trans. (2006) 34: 223-227). ACCexists as two tissue-specific isoforms, a single-chain 265 kDa protein(ACC1), and a 280 kDa protein (ACC2) (See, Waldrop, G. L. et al.,“Targeting acetyl-CoA carboxylase for anti-obesity therapy,” Curr. Med.Chem.—Immun., Endoc. & Metab. Agents (2002) 3: 229-234).

In mammalian cells, ACC1 is present within the cytosol while ACC2localizes to mitochondria. Generally, ACC1 is responsible for long-chainfatty acid synthesis while mitochondrial ACC2 acts to inhibit fatty acidoxidation. Expression of the ACC isoforms is tissue-specific andresponsive to hormones and nutritional status. ACC1 is expressed at highlevels in lipogenic tissues, notably in adipose, liver, and lactatingmammary gland. ACC2 is a minor component of hepatic ACC and is thepredominant isoform expressed, albeit at relatively low levels, in heartand skeletal muscle. Active ACC has been shown to be present in humansebaceous glands, although the ACC isoform expression pattern has notyet been described (see, Smythe, C. D. et al., “The activity of HMG-CoAreductase and acetyl-CoA carboxylase in human apocrine sweat glands,sebaceous glands, and hair follicles is regulated by phosphorylation andby exogenous cholesterol,” J. Invest. Dermatol. (1998) 111:139-148). ACCand other fatty acid and cholesterol synthesis-regulating enzymes havebeen shown to be positively regulated by androgen, a key factorcontributing to the increased sebum production at puberty as well as theexpression of acne (see, Rosignoli, C. et al., “Involvement of the SREBPpathway in the mode of action of androgens in sebaceous glands in vivo”,Exp. Dermatol. (2003) 12:480-489).

ACC also catalyzes the first committed and regulated step in fatty acidsynthesis in bacteria. Since membrane lipid biogenesis is essential forbacterial growth, inhibition of ACC activity may potentially decreasethe growth of bacteria normally present within a comedone.

Long-chain (16-20 carbons) fatty acid acyl-CoA thioesters have beenfound to be potent physiological end-product inhibitors of mammalianACC.

TOFA (5-(tetradecyloxy)-2-furancarboxylic acid) is a known hypolipidemiccompound having the following structure:

TOFA and pharmaceutically acceptable salts thereof are described andclaimed in U.S. Pat. No. 4,110,351 (the disclosure of which isincorporated in full by reference). TOFA has been shown to reduce plasmatriglyceride levels in both rats and monkeys (see, e.g., Parker, R. A.et al., J. Med. Chem. (1977), Vol. 20, pp. 781-791) and to inhibithepatic fatty acid synthesis (see, e.g., Ribereau-Gayon, G., FEBS Lett.(1976), Vol. 62, No. 309-312; Panek, E. et al., Lipids (1977), Vol. 12,pp. 814-818; Kariya, T. et al., Biochem. Biophys. Res. Commun. (1978),Vol. 80, pp. 1022-1024; and Harris, R. A. et al., Hormones and EnergyMetabolism (Klachko, D. M. et al., eds.), Vol. III, pp. 17-42.

TOFA, when converted intracellularly to its acyl-CoA thioester, inhibitsACC activity with a mechanism similar to long chain fatty acyl-CoA's,the physiological end-product inhibitors of ACC (see, McCune, S. A. etal., J. Biol. Chem. (1979), Vol. 254, No. 20, pp. 10095-10101. As afatty acid mimetic, TOFA may exert multiple effects in sebaceous glanddisorders by lowering sebum production and potentially affecting thegrowth of pathogenic bacteria at the treatment site.

Methods of using TOFA to inhibit sebaceous gland hyperactivity and inthe treatment of acne and inflammation are known. See, for example, PCTPublished Patent Application No. WO 2008/058034.

Analogs of TOFA, such as the compounds of the invention, are disclosedherein as effective inhibitors of sebaceous gland activity, and aretherefore useful in treating a mammal, preferably a human, having adermatological disorder or condition characterized by sebaceous glandhyperactivity, such as acne. The analogs of TOFA disclosed herein mayalso be useful in treating a mammal having a disorder or conditioncharacterized by inflammation by reducing T cell proliferation andcytokine secretion.

Preparation of the Compounds of the Invention

The following Reaction Schemes represent methods of preparing thecompounds of the invention, i.e., compounds of formula (I):

wherein R¹ is as defined above in the Summary of the Invention, as astereoisomer or as a mixture thereof, or a pharmaceutically acceptablesalt thereof.

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Protective Groups in Organic Synthesis (2006), 4^(th)Ed., Wiley. The protecting group may also be a polymer resin such as aWang resin or a 2-chlorotrityl-chloride resin.

It is understood that one skilled in the art would be able to make thecompounds of the invention by methods similar to the ones describedbelow in the Reaction Schemes or by methods known to one skilled in theart. It is also understood that one skilled in the art would be able tomake in a similar manner as described below other compounds of theinvention not specifically illustrated below by using the appropriatestarting components and modifying the parameters of the synthesis asneeded. In general, starting components may be obtained from sourcessuch as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, MatrixScientific, TCI, and Fluorochem USA, etc. or synthesized according tosources known to those skilled in the art (see, e.g., Smith, M. B. andJ. March, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedherein. TOFA is commercially available, for example, from CedarlaneLaboratories, Inc.

The compounds of the present invention can be prepared as in ReactionScheme 1, where R², R⁴ and R⁵ are each as described above in the Summaryof the Invention, by activating the carboxylic group of5-(tetradecyloxy)furan-2-carboxylic acid (TOFA) with a suitable reagentincluding but not limited to: oxalyl chloride, thionyl chloride, aceticanhydride, trifluoroacetic anhydride, toluenesulfonyl chloride,hydroxysuccinamide, hydroxybenzotriazole, dicyclohexylcarbodiimide, orcarbonyldiimidazole. The activated acid compound is generally preparedat temperatures of between 0° C. and ambient and may be isolated or maybe reacted in situ with a suitable alcohol or sulfonamide in thepresence of a base (triethylamine, pyridine, etc.). The product from thereaction can be isolated and purified employing standard techniques suchas solvent extraction, chromatography, crystallization, distillation,and the like.

The compounds of the present invention can also be prepared as outlinedin Reaction Scheme 2 where each R², R³, R⁵ and R⁶ are as described abovein the Summary of the Invention. TOFA can be reacted with an alkylatingagent (either purchased commercially or prepared using techniques wellknown in the art) having a suitable leaving group (halide, triflate,tosylate, mesylate, and the like) in the presence of a suitable base(including but not limited to potassium carbonate, cesium carbonate,tetrabutylammonium hydroxide, triethylamine, etc.). The reactions can becarried out in a suitable solvent such as N,N-dimethylformamide and areusually performed at a temperature between ambient and 70° C. Theproduct from the reaction can be isolated and purified employingstandard techniques such as solvent extraction, chromatography,crystallization, distillation, and the like.

The compounds of the present invention can also be prepared as shownabove in Reaction Scheme 3. TOFA can be reacted with a linker containingtwo suitable leaving groups (halide, triflate, tosylate, mesylate, andthe like). The initial reaction is performed as in Reaction Scheme 2above. The product of this reaction is then reacted with a suitablenucleophile including but not limited to amines (shown above), alcoholsor phenols in a suitable solvent such as DMF or THF. The reaction isgenerally performed at ambient temperature for 12 hrs in the presence ofa suitable base which may be tetrabutylammonium hydroxide, excess of theamine nucleophile, triethylamine, or the like. The product from thereaction can be isolated and purified employing standard techniques suchas solvent extraction, chromatography, crystallization, distillation,and the like.

In some cases the final product of the Reaction Schemes shown above maybe further modified, for example by manipulation of substituents. Thesemanipulations may include, but are not limited to, oxidation, reduction,alkylation, acylation and hydrolysis, as needed to prepare the compoundsof the invention. Such manipulations are within the knowledge of oneskilled in the organic chemistry field. These manipulations may alsoinclude the removal of a protecting group such as a Boc group, atetrahydropyran group or the like by methods outlined in T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis”, SecondEdition, John Wiley and Sons, New York, 1991.

All compounds of the invention as prepared above and below which existin free base or acid form may be converted to their pharmaceuticallyacceptable salt by treatment with the appropriate inorganic or organicbase or acid by methods known to one skilled in the art. Salts of thecompounds prepared herein may be converted to their free base or acid bystandard techniques known to one skilled in the art.

The following Synthetic Examples, which are directed to the preparationof the compounds of formula (I), are provided as a guide to assist inthe practice of the invention, and are not intended as a limitation onthe scope of the invention. Mass spectrometer samples were analyzed on aMicroMass mass spectrometer operated in single MS mode with electrosprayionization. Samples were introduced into the mass spectrometer usingchromatography. 1H NMR spectra were recorded at 400 MHz using a Brukerinstrument or at 300 MHz using a Varian instrument. Elemental analysiswas performed by Canadian Microanalytical Ltd., Delta, BC, Canada.

SYNTHETIC EXAMPLE 1 Synthesis of 2,2,2-trifluoroethyl5-(tetradecyloxy)furan-2-carboxylate

To a stirred, room temperature suspension of5-(tetradecyloxy)furan-2-carboxylic acid (1.3 g, 4.0 mmol) in CH₂Cl₂ (40mL) was added N,N′-dicyclohexylcarbodiimide (0.990 g, 4.8 mmol),N,N-dimethylaminopyridine (0.488 g, 4.0 mmol) and 2,2,2-trifluoroethanol(0.875 mL, 12.0 mmol). The flask was capped and stirring was continuedfor 16 hrs at which time TLC (10% EtOAc in Hexanes R_(f)=0.05 (SM) and0.25 (Prod)) indicated complete consumption of the starting material.The resulting suspension was diluted with CH₂Cl₂ (40 mL), filtered andconcentrated. This crude material was purified by flash chromatographyeluting with 5-20% EtOAc in Hexanes. The resulting solid was furtherpurified by recrystallization in 30 mL of hot 2-propanol with theaddition of a minimum amount of water to yield 1.13 g (70%) of the titlecompound as white needles. MS (m/z, ES−): 406.0 (M−1, 100%); EA foundfor C₂₃H₃₆F₃NO₂: C: 62.20, H: 8.18; calcd: C: 62.05, H: 8.18; ¹H NMR(400 MHz, DMSO-d₆) δ: 7.4 (d, 1H), 5.7 (d, 1H), 4.9 (q, 2H), 4.2 (t,2H), 1.50-1.57 (m, 2H), 1.10-1.20 (m, 22H), 0.85 (t, 3H).

SYNTHETIC EXAMPLE 2 Synthesis of 2,2,2-trichloroethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as described in Example 1 starting from0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.196mL (2.04 mmol) of 2,2,2-trichloroethanol. ¹H NMR (400 MHz, DMSO-d₆) δ:7.4 (d, 1H), 5.74 (d, 1H), 5.03 (s, 2H), 4.19 (t, 2H), 1.7 (p, 2H),1.2-1.5 (m, 22H), 0.85 (t, 3H).

SYNTHETIC EXAMPLE 3 Synthesis of isopropyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as described in Example 1 starting from0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.161mL (2.1 mmol) of 2-propanol. MS (m/z, ES+): 366.30 (M+, 100%); ¹H NMR(400 MHz, DMSO-d₆) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.0 (p, 1H), 4.1 (t,2H), 1.7 (p, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t,3H).

SYNTHETIC EXAMPLE 4 Synthesis of methyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as described in Example 1 starting from0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.083mL (2.1 mmol) of methanol. MS (m/z, ES+): 339.34 (M+1, 100%).

SYNTHETIC EXAMPLE 5 Synthesis of 2-bromoethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as described in Example 1 starting from0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.150mL (2.1 mmol) of 2-bromoethanol. MS (m/z, ES+): 446.30 (⁷⁹BrM+1, 100%),448.30 (⁸¹BrM+1, 80%); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.30 (d, 1H), 5.67(d, 1H), 4.49 (t, 2H), 4.16 (t, 2H), 3.73 (t, 2H), 1.72 (p, 2H),1.3-1.45 (m, 2H), 1.25 (s, 20H), 0.85 (t, 3H); EA found for C₂₁H₃₅BrO₄:C: 58.93, H: 8.52; calcd: C: 58.47, H: 8.18.

SYNTHETIC EXAMPLE 6 Synthesis of5-(tetradecyloxy)-N-tosylfuran-2-carboxamide

The title compound was prepared as described in Example 1 starting from0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.361g (2.1 mmol) of 4-methylbenzenesulfonamide. MS (m/z, ES−): 476.63 (M−1,100%).

SYNTHETIC EXAMPLE 7 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl5-(tetradecyloxy)furan-2-carboxylate

To a stirred, room temperature solution of5-(tetradecyloxy)furan-2-carboxylic acid (0.228 g, 0.70 mmol) in DMF (4mL) was added potassium carbonate (0.146 g, 1.05 mmol) and4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (0.160 g, 0.84 mmol). Thereaction vessel was capped and stirring was continued for 14 hrs atwhich time TLC ((20% EtOAc in Hexanes R_(f)=0.10 (SM) and 0.40 (Prod))indicated complete consumption of the starting material. The reactionwas quenched by the addition of water (5 mL), brine (5 mL) and EtOAc (30mL). The biphasic mixture was transferred to a separatory funnel and theorganic phase was extracted 3 times with brine (3×10 mL). The organicphase was dried and concentrated to give a colourless oil. The resultingcrude material was purified by flash chromatography eluting with 5-20%EtOAc in hexanes to yield a colourless syrup that solidified onstanding. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.1 (s,2H), 4.1 (t, 2H), 2.18 (s, 3H), 1.6-1.8 (m, 2H), 1.3-1.4 (m, 2H), 1.23(d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).

SYNTHETIC EXAMPLE 8 Synthesis of 1-(benzyl(methyl)carbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate

A. 1-chloroethyl benzyl(methyl)carbamate

To a vigorously stirred suspension of N-methylbenzylamine (0.260 mL, 2mmol) in EtOAc (3 mL) and 3 mL of saturated NaHCO₃ solution was added1-chloroethyl chloroformate (0.160 mL, 2 mmol). Effervescence wasobserved. Once gas production had ceased, the reaction mixture wasdiluted with hexanes (10 mL). The aqueous phase was removed and theorganic phase was washed with brine (5 mL), dried and concentrated togive the crude product as an oil (˜0.250 g). The compound was used inthe subsequent step without further purification.

B. 1-(benzyl(methyl)carbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate

The above prepared 1-chloroethyl benzyl(methyl)carbamate was dissolvedin N,N-dimethylformamide (5 mL) and then5-(tetradecyloxy)furan-2-carboxylic acid (0.180 g, 0.544 mmol),tetrabutylammonium hydroxide pentahydrate (0.209 g, 0.60 mmol), andsodium iodide (˜15 mg) were added to the reaction vessel. The resultingsuspension was heated to 60° C. with stirring for 14 hrs. HPLC analysisof the reaction solution indicated that all of the starting material hadbeen converted to a product of lower polarity. The reaction was thenquenched with brine (5 mL), water (5 mL) and EtOAc (70 mL). The organicphase was washed successively with water (30 mL) and brine (30 mL) andthen dried and concentrated. The resulting crude material was purifiedby flash chromatography eluting with EtOAc in hexanes, 5-20% to yield0.120 g (43%) of the title compound as a slightly brown oil. ¹H NMR (300MHz, CDCl₃) δ: 7.15-7.40 (m, 6H), 7.05 (p, 1H), 5.30 (d, 1H), 4.40-4.60(m, 2H), 4.10 (t, 2H), 2.85 (d, 3H) 1.7-1.9 (m, 2H), 1.79 (p, 2H),1.55-1.62 (m, 3H), 1.18-1.50 (m, 22H), 0.89 (t, 3H).

SYNTHETIC EXAMPLE 9 Synthesis of1-((2-ethoxy-2-oxoethyl)(methyl)carbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.267 g (1.8mmol) of sarcosine ethyl ester hydrochloride and 4 mL of saturatedNaHCO₃ solution. ¹H NMR (300 MHz, CDCl₃) δ: 7.18 (t, 1H), 6.98 (dq, 1H),5.3 (d, 1H), 4.03-4.23 (m, 5H), 3.8-3.9 (m, 1H), 2.98 (s, 3H), 1.75 (p,2H), 1.52-1.6 (m, 3H), 1.2-1.5 (m, 27H), 0.85 (t, 3H).

SYNTHETIC EXAMPLE 10 Synthesis of (2S)-2-benzyl1-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)pyrrolidine-1,2-dicarboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.435 g (1.8mmol) of L-benzylproline hydrochloride and 4 mL of saturated NaHCO₃solution. The compound was isolated as a mixture of two diastereomers.¹H NMR (300 MHz, CDCl₃) δ: 7.25-7.4 (m, 5H), 6.9-7.2 (m, 2H), 5.0-5.3(m, 2H), 4.35-4.45 (m, 1H), 4.0-4.18 (m, 2H), 3.4-3.65 (m, 2H), 2.1-2.3(m, 1H), 1.8-2.0 (m, 2H), 1.65-1.8 (m, 2H), 1.45-1.6 (m, 3H), 1.2-1.5(m, 24H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 11 Synthesis of1-(4-phenylcyclohexanecarbonyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.303 g (1.8mmol) of 1-phenyl piperazine and 4 mL of saturated NaHCO₃ solution. ¹HNMR (300 MHz, CDCl₃) δ: 7.25-7.35 (m, 2H), 7.20 (d, 1H, J=4 Hz), 7.04(q, 1H, J=5 Hz), 6.85-6.95 (m, 3H), 5.30 (d, 1H, J=4 Hz), 4.15 (app t,2H, J=3.5 Hz), 3.63 (br t, 4H), 3.18 (br s, 4H), 1.8 (p, 2H, J=8 Hz),1.60 (d, 3H, J=6 Hz), 1.20-1.5 (m, 22H), 0.87 (t, 3H, J=7 Hz).

SYNTHETIC EXAMPLE 12 Synthesis of1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl3-phenylpyrrolidine-1-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.167 g (1.8mmol) of 3-phenyl pyrrolidine and 4 mL of saturated NaHCO₃ solution. Thecompound was isolated as a mixture of four diastereomers. ¹H NMR (300MHz, CDCl₃) δ: 7.18-7.3 (m, 5H), 7.2 (q, 1H), 6.93 (d, 1H), 5.3 (d, 1H),4.12 (t, 2H), 3.1-4.0 (m, 5H), 2.2-2.35 (m, 1H), 1.95-2.05 (m, 1H), 1.75(t, 2H), 1.5-1.65 (m, 3H), 1.2-1.5 (m, 22H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 13 Synthesis of1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl3,4-dihydroisoquinoline-2(1H)-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.305 g (1.8mmol) of 1,2,3,4-tetrahydroisoquinoline hydrochloride and 4 mL ofsaturated NaHCO₃ solution. ¹H NMR (300 MHz, CDCl₃) δ: 7.0-7.2 (m, 6H),5.3 (d, 1H), 4.6 (d, 2H), 4.1 (t, 2H), 3.6-3.75 (m, 2H), 2.8-2.87 (m,2H), 1.75 (p, 2H), 1.5-1.62 (m, 3H), 1.2-1.5 (m, 22H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 14 Synthesis of1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl piperidine-1-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.178 mL (1.8mmol) of piperidine and 4 mL of saturated NaHCO₃ solution. ¹H NMR (300MHz, CDCl₃) δ: 7.18 (d, 1H), 6.98 (q, 1H), 5.3 (d, 1H), 4.08-4.18 (m,2H), 3.38-3.42 (m, 4H), 1.5-1.8 (m, 33H), 0.89 (t, 3H).

SYNTHETIC EXAMPLE 15 Synthesis of1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl morpholine-4-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.157 mL (1.8mmol) of morpholine and 4 mL of saturated NaHCO₃ solution. ¹H NMR (300MHz, CDCl₃) δ: 7.18 (d, 1H), 7.05 (q, 1H), 5.32 (d, 1H), 4.1 (t, 2H),3.6-3.6 (m, 4H), 3.45-3.55 (m, 4H), 1.75 (p, 2H), 1.5-1.65 (m, 3H),1.2-1.5 (m, 22H), 0.85 (t, 3H).

SYNTHETIC EXAMPLE 16 Synthesis of 1-tert-butyl4-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)piperazine-1,4-dicarboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.335 mg (1.8mmol) of tert-butyl 1-piperazine carboxylate and 4 mL of saturatedNaHCO₃ solution. ¹H NMR (300 MHz, CDCl₃) δ: 7.2 (d, 1H), 6.97 (q, 1H),5.3 (d, 1H), 4.1 (t, 2H), 3.4 (br s, 8H), 1.75 (p, 2H), 1.5-1.6 (m, 3H)1.5 (s, 9H), 1.2-1.5 (m, 22H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 17 Synthesis of 1-(dicyclohexylcarbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 8, Steps 1 and 2 startingwith 0.20 mL (1.8 mmol) of 1-chloroethylchloroformate, 0.220 mg (1.8mmol) of dicyclohexylamine and 3 mL of saturated NaHCO₃ solution. ¹H NMR(300 MHz, CDCl₃) δ: 7.1 (d, 1H), 7.0 (q, 1H), 5.3 (d, 1H), 4.05-4.15 (m,2H), 3.6 (br s, 1H), 3.2 (br s, 1H), 1.65-1.8 (m, 10H), 1.55-1.65 (m,11H), 1.2-1.5 (m, 24H), 1.0-1.2 (m, 2H), 0.8 (t, 3H).

SYNTHETIC EXAMPLE 18 Synthesis of 2-(dimethylamino)ethyl5-(tetradecyloxy)furan-2-carboxylate

To a solution of 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate(0.186 g, 0.43 mmol) (prepared in Example 5) in THF at 0° C. was addeddimethylamine (1 mL of a 2M solution in THF, 2.15 mmol) with stirring.The solution was allowed to warm to room temperature and stirring wascontinued for 12 hrs at which time the reaction was concentrated todryness. The crude material was purified by flash chromatography elutingwith ethyl acetate in hexanes (5-35%) to yield 0.121 g (71%) of thetitle compound as a waxy, colourless solid. MS (m/z, ES+): 396.29 (M+1,100%); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.2 (d, 1H), 5.6 (d, 1H), 4.23 (t,2H), 4.13 (t, 2H), 2.53 (t, 2H), 2.18 (s, 6H), 1.7 (p, 2H), 1.2-1.5 (m,22H), 0.85 (t, 3H).

SYNTHETIC EXAMPLE 19 Synthesis of 3-morpholinopropyl5-(tetradecyloxy)furan-2-carboxylate

A. 3-chloropropyl 5-(tetradecyloxy)furan-2-carboxylate

To a vigorously stirred suspension of5-(tetradecyloxy)furan-2-carboxylic acid (0.650 g, 2.0 mmol) in 10 mL ofN,N-dimethylformamide was added 3-chlorobromopropane (0.618 mL, 6.0mmol), tetrabutylammonium hydroxide pentahydrate (0.734 g, 4.2 mmol) andsodium iodide (˜20 mg). The suspension appeared to go into solutionbriefly, and then a very finely dispersed white precipitate wasobserved. The reaction was allowed to stir for 12 hrs. The suspensionwas then diluted with EtOAc (100 mL), brine (50 mL) and water (50 mL).The phases were separated and the organic phase was washed with water(50 mL) and brine (50 mL). The organic phase was then dried andconcentrated to yield 0.554 g of the title compound. This material wasused in the subsequent step without further purification.

B. 3-(piperidin-1-yl)propyl 5-(tetradecyloxy)furan-2-carboxylate

To a solution of the above prepared 3-chloropropyl5-(tetradecyloxy)furan-2-carboxylate (0.272g, 0.68 mmol) in 6 mL ofN,N-dimethylformamide was added morpholine (0.535 mL, 6.1 mmol) andsodium iodide (10 mg). The resulting solution was stirred at 55° C. for36 hrs at which time HPLC analysis of the reaction mixture indicatednear complete consumption of the starting material. The solution wasdiluted with EtOAc (30 mL), brine (10 mL) and water (10 mL) such thatboth phases were clear solutions. The phases were separated and theorganic phase was washed with water (20 mL) and brine (20 mL) and thendried and concentrated. The crude material was purified by flashchromatography eluting with 5-40% EtOAc in hexanes to yield 0.217 g ofthe title compound. ¹H NMR (300 MHz, CDCl₃) δ: 7.10 (d, 1H), 5.30 (d,1H), 4.30 (t, 2H), 4.10 (t, 2H), 3.7 (t, 4H), 2.40-2.50 (m, 6H), 1.90(p, 2H), 1.76 (p, 2H), 1.18-1.50 (m, 22H), 0.89 (t, 3H).

SYNTHETIC EXAMPLE 20 Synthesis of 2-(benzyl(methyl)amino)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate

A. N-benzyl-2-chloro-N-methylacetamide

To a vigorously stirred suspension of N-methylbenzylamine (0.260 mL, 2mmol) in EtOAc (3 mL) and 3 mL of saturated NaHCO₃ solution was addedchloroacetyl chloride (0.160 mL, 2 mmol). Effervescence was observed.Once gas production had ceased, the reaction mixture was diluted withhexanes (10 mL). The phases were separated and the organic phase waswashed with brine (5 mL), dried and concentrated to yield ˜0.250 g ofthe title compound as an oil. The crude material was used in thesubsequent step without further purification.

B. 2-(benzyl(methyl)amino)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate

The above prepared N-benzyl-2-chloro-N-methylacetamide (0.250 g) wasdissolved in 10 mL of N,N-dimethylformamide. To this solution were added5-(tetradecyloxy)furan-2-carboxylic acid (0.180 g, 0.544 mmol),tetrabutylammonium hydroxide pentahydrate (0.209 g, 0.554 mmol), andsodium iodide (˜15 mg). The suspension was heated to 60° C. withstirring for 14 hrs. The reaction was quenched with brine (5 mL), water(5 mL) and EtOAc (40 mL). The phases were separated and the organicphase was further diluted with EtOAc (30 mL), washed successively withwater (30 mL) and brine (30 mL) and then dried and concentrated. Theresulting crude material was purified by flash chromatography elutingwith 5-20% EtOAc in hexanes to give the desired compound as a viscousoil. The material was further purified by recrystallization from2-propanol and water to yield 0.130 g (52%) of the title compound. ¹HNMR (300 MHz, CDCl₃) δ: 7.20-7.40 (m, 6H), 5.30-5.35 (m, 1H), 4.92 (s,2H), 4.50-4.61 (app d, 2H), 4.10 (m, 2H), 2.90-2.98 (app d, 3H), 1.79(p, 2H), 1.18-1.50 (m, 22H), 0.89 (t, 3H).

SYNTHETIC EXAMPLE 21 Synthesis of tert-butyl4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine-1-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.373 g (2.0 mmol) of tert-butyl 1-piperazine carboxylate and 0.160mL (2 mmol) of chloroacetyl chloride except that the reaction mixture inStep 1 was diluted in EtOAc rather than hexanes. ¹H NMR (300 MHz, CDCl₃)δ: 7.22 (d, 1H), 5.3 (d, 1H), 4.85 (s, 2H), 4.15 (t, 2H), 3.55-3.65 (m,2H), 3.4-3.52 (m, 6H), 1.75 (p, 2H), 1.45 (s, 9H), 1.2-1.5 (m, 22H), 0.8(t, 3H).

SYNTHETIC EXAMPLE 22 Synthesis of 2-(dicyclohexylamino)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.244 mL (2.0 mmol) of dicyclohexylamine and 0.160 mL (2 mmol) ofchloroacetyl chloride except that the reaction mixture in Step 1 wasdiluted in EtOAc rather than hexanes. ¹H NMR (300 MHz, CDCl₃) δ: 7.2 (d,1H), 5.3 (d, 1H), 4.8 (s, 2H), 4.1-4.18 (m, 2H), 3.22 (t, 2H), 2.9-3.05(m, 2H), 2.3-2.5 (m, 2H), 1.1-1.9 (m, 40H), 0.83 (t, 3H).

SYNTHETIC EXAMPLE 23 Synthesis of2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.337 g (2.0 mmol) of 1-cyclohexylpiperazine and 0.160 mL (2 mmol)of chloroacetyl chloride except that the reaction mixture in Step 1 wasdiluted in EtOAc rather than hexanes. ¹H NMR (300 MHz, CDCl₃) δ: 7.22(d, 1H), 5.3 (d, 1H), 4.9 (s, 2H), 4.1 (t, 2H), 3.6 (t, 2H), 3.4 (t,2H), 2.57 (p, 4H), 2.2-2.35 (m, 1H), 1.5-1.8 (m, 6H), 1.2-1.5 (m, 28H),0.83 (t, 3H).

SYNTHETIC EXAMPLE 24 Synthesis of2-oxo-2-(4-phenylpiperzin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.324 g (2.0 mmol) of 1-phenyl piperazine and 0.160 mL (2 mmol) ofchloroacetyl chloride except that the reaction mixture in Step 1 wasdiluted in EtOAc rather than hexanes. The title compound was furtherpurified by recrystallization from isopropanol and water. ¹H NMR (300MHz, CDCl₃) δ: 7.23-7.35 (m, 4H), 6.9 (d, 2H), 5.34 (d, 1H), 4.95 (s,2H), 4.13 (t, 2H), 3.78-3.82 (m, 2H), 3.69-3.63 (m, 2H), 3.15-3.25 (m,4H), 1.75 (p, 2H), 1.2-1.5 (m, 22H), 0.86 (t, 3H).

SYNTHETIC EXAMPLE 25 Synthesis of2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl5-tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.307 g (2.0 mmol) of sarcosine ethyl ester hydrochloride and 0.160mL (2 mmol) of chloroacetyl chloride except that the reaction mixture inStep 1 was diluted in EtOAc rather than hexanes. ¹H NMR (300 MHz, CDCl₃)δ: 7.23 (d, 1H), 5.32 (d, 1H), 4.95 and 4.8 (2s of rotamers, 2H),4.05-4.25 (m, 6H), 3.1 and 3.0 (2s of rotamers, 3H), 1.75 (p, 2H),1.2-1.5 (m, 25H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 26 Synthesis of2-oxo-2-(piperidin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.198 mL (2.0 mmol) of piperidine and 0.160 mL (2 mmol) ofchloroacetyl chloride except that the reaction mixture in Step 1 wasdiluted in EtOAc rather than hexanes. The crude material isolated inStep 2 was purified by recrystallization from isopropanol. ¹H NMR (300MHz, CDCl₃) δ: 7.22 (d, 1H), 5.35 (d, 1H), 4.87 (s, 2H), 4.15 (t, 2H),3.55-3.6 (m, 2H), 3.3-3.4 (m, 2H), 1.75 (p, 2H), 1.5-1.7 (m, 6H),1.2-1.5 (m, 22H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 27 Synthesis of 2-morpholino-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.157 mL (2.0 mmol) of morpholine and 0.160 mL (2 mmol) ofchloroacetyl chloride except that the reaction mixture in Step 1 wasdiluted in EtOAc rather than hexanes. ¹H NMR (300 MHz, CDCl₃) δ: 7.23(d, 1H), 5.35 (d, 1H), 4.86 (s, 2H), 4.15 (t, 2H), 3.68-3.75 (m, 4H),3.6-3.65 (m, 2H), 3.4-3.45 (m, 2H), 1.75 (p, 2H), 1.2-1.5 (m, 22H), 0.9(t, 3H).

SYNTHETIC EXAMPLE 28 Synthesis of2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.339 g (2.0 mmol) of 1,2,3,4-tetrahydroisoquinoline hydrochlorideand 0.160 mL (2 mmol) of chloroacetyl chloride except that the reactionmixture in Step 1 was diluted in a 1:1 mixture of hexanes:EtOAc ratherthan hexanes. ¹H NMR (300 MHz, CDCl₃) δ: 7.05-7.25 (m, 5H), 5.32 (d,1H), 4.95 (2s of rotamers, 2H), 4.65 and 4.7 (2s of rotamers, 2H), 4.15(t, 2H), 3.83 and 3.63 (2t of rotamers, 2H), 2.92 and 2.85 (2t ofrotamers, 2H), 1.78 (p, 2H), 1.2-1.5 (m, 22H), 0.9 (t, 3H).

SYNTHETIC EXAMPLE 29 Synthesis of (S)-benzyl1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate

The title compound was prepared as in Example 20, Steps 1 and 2 startingwith 0.483 g (2.0 mmol) of L-proline benzyl ester hydrochloride and0.160 mL (2 mmol) of chloroacetyl chloride except that the reactionmixture in Step 1 was diluted in EtOAc rather than hexanes. The crudematerial isolated in Step 2 was purified by recrystallization fromisopropanol. ¹H NMR (300 MHz, CDCl₃) δ: 7.23-7.25 (m, 5H), 7.2 (d, 1H),5.3 (d, 1H), 5.15 (d, 2H), 4.2-5.0 (m, 3H), 4.13 (t, 2H), 3.5-3.7 (m,2H), 1.95-2.3 (m, 4H), 1.75 (p, 2H), 1.2-1.5 (m, 22H), 0.83 (t, 3H).

SYNTHETIC EXAMPLE 30 Synthesis of 4-methyl pentyl5-(tetradecyloxy)furan-2-carboxylate

To a vigorously stirred suspension of5-(tetradecyloxy)furan-2-carboxylic acid (0.162 g, 0.5 mmol) in 10 mL ofN,N-dimethylformamide was added 1-bromo-4-methylpentane (0.247 g, 1.5mmol), cesium carbonate (0.243 g, 0.75 mmol) and sodium iodide (˜20 mg).The suspension appeared to go into solution briefly, and then a veryfinely dispersed white precipitate was observed. The reaction wasallowed to stir for 12 hrs at which time HPLC analysis of the reactionsolution indicated complete conversion of TOFA to a less polar product.The suspension was diluted with EtOAc (40 mL), brine (20 mL) and water(20 mL). The phases were separated and the organic phase was washed withwater (20 mL) and brine (20 mL) and then dried and concentrated. Theresulting crude material was purified by flash chromatography elutingwith 0-20% EtOAc in hexanes to yield 0.127 g (62%) of the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.22(t, 2H), 4.10 (t, 2H), 1.18-1.80 (m, 29H), 0.89 (t, 9H).

SYNTHETIC EXAMPLE 31 Synthesis of 3-(tetrahydro-2H-pyran-2-yloxy)propyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 30 starting with 0.335 g(1.5 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 0.162 g (0.5mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid. ¹H NMR (300 MHz,CDCl₃) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.59-4.62 (m, 1H), 4.40 (app t,2H), 4.10 (t, 2H), 3.80-3.90 (m, 2H), 3.40-3.60 (m, 2H), 2.05 (p, 2H),1.20-1.85 (m, 30H), 0.89 (t, 3H).

SYNTHETIC EXAMPLE 32 Synthesis of 2-morpholinoethyl5-(tetradecyloxy)furan-2-carboxylate

The title compound was prepared as in Example 30 starting with 0.224 g(1.2 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.162 g (0.5mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid with the exceptionthat a total of 0.730 g of cesium carbonate was added to neutralize thehydrochloride. ¹H NMR (300 MHz, CDCl₃) δ: 7.15 (d, 1H), 5.30 (d, 1H),4.40 (t, 2H), 4.10 (t, 2H), 3.70 (app t, 4H), 2.70 (t, 2H), 2.55 (app t,4H), 1.80 (p, 2H), 1.18-1.55 (m, 22H), 0.89 (t, 3H).

SYNTHETIC EXAMPLE 33 Synthesis of2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid

To a cooled (0° C.) and stirred suspension of5-(tetradecyloxy)furan-2-carboxylic acid (0.324 g, 1 mmol) in 10 mL ofCH₂Cl₂ was added oxalyl chloride (0.135 mL, 1.5 mmol) and 2 drops ofN,N-dimethylformamide. Immediate effervescence was observed. Thesolution was allowed to warm to room temperature with continued stirringuntil such a time that gas evolution had ceased and all suspended solidshad dissolved. The solution was then cooled to 0° C. once more andsalicylic acid (0.180 g, 1.3 mmol) and Et₃N (3 mL) were added to therapidly stirred reaction. After stirring for 2 hrs, the reaction wasdiluted with EtOAc (100 mL) and the organic phase was washed with 1M HCl(2×100 mL) and brine (100 mL) and then dried and concentrated to give awhite solid residue. The crude material was purified by flashchromatography eluting with 5-40% EtOAc in Hexanes with 1% AcOH. Theresulting material was further purified by recrystallization from CH₂Cl₂and hexanes to yield 0.225 g (57%) of the title compound as a whitecrystalline material. ¹H NMR (300 MHz, CDCl₃) δ: 8.08 (dd, 1H), 7.62(dt, 1H), 7.32-7.38 (m, 2H), 7.24 (dd, 1H), 5.39 (d, 1H), 4.18 (t, 2H),1.80 (p, 2H), 1.2-1.5 (m, 22H), 0.88 (t, 3H).

Testing of the Compounds of the Invention

Study of human sebocyte function has been relatively restricted due tothe lack of suitable cell lines. Recently, SZ95 sebocytes were preparedusing human facial sebaceous gland cells transfected with a plasmidcontaining the coding region for the Simian virus-40 large T antigen(see, Zouboulis, C. C. et al., J. Invest. Dermatol. (1999), Vol. 113,pp. 1011-1020). SZ95 cells express a number of molecules typicallyassociated with human sebocytes. Functional studies showed synthesis ofthe sebaceous lipids squalene and wax esters as well as triglyceridesand free fatty acids (see, Zouboulis C C, Seltmann H, Neitzel H, OrfanosC E. Establishment and characterization of an immortalized humansebaceous gland cell line (SZ95). J. Invest Dermatol. (1999)113:1011-1020).

Thus, SZ95 cells are capable of recapitulating many aspects of sebocytegrowth and differentiation (see, Wrobel, A. et al., “Differentiation andapoptosis in human immortalized sebocytes”, J. Invest Dermatol. (2003)120:175-181).

Treatment with arachidonic acid (AA) reproducibly increased SZ95sebocyte lipid levels approximately 5-fold using a 96-well microtiterplate format. SZ95 cells can be used to identify compounds withsebum-inhibitory potential, such as Accutane® and cholesterol synthesisinhibitors (statins), both of which demonstrated the ability to lowerlipid production by these cells (See, Tsukada, M. et al., “13-cisretinoic acid exerts its specific activity on human sebocytes throughselective intracellular isomerization to all-trans retinoic acid andbinding to retinoid acid receptors”, J. Invest. Dermatol. (2000)115:321-327).

The administration of compounds of the invention may also inhibitseveral parameters related to T cell activation including proliferationand secretion of immune/inflammation-regulating cytokines. Accordingly,analogs of TOFA would be useful agents in treating dermatologicaldisorders or conditions characterized by inflammation, by reducing Tcell proliferation and cytokine secretion, for example, in the treatmentof inflammatory acne.

In vivo testing for evaluating potential acne treatment can be conductedusing the following hamster assays because hamster ear sebaceous glandshave a close resemblance to those of humans in terms of structure,biochemistry and physiology.

In Vivo Anti-Sebaceous Gland Activity Testing

The Syrian golden hamster (Oryctolagus cuniculus) ear sebaceous glandmodel was used to evaluate the effect of repeat application of TOFA andTOFA analogs. Male animals were employed since they have largersebaceous glands than females a consequence of their higher endogenouslevels of androgenic hormones. To define compound effects,cross-sections prepared from hamster ears were treated with the neutrallipid-specific stain Oil Red O. Staining results were compared to theuntreated ear of the same animal in order to account for any changes inthe overall physiological state of the animal as well as potentialsystemic effects stemming from local drug application.

Animal Treatment and Monitoring.

Typically, compounds were prepared and applied in 40% dimethyl acetamide(DMA)/30% acetone/30% ethanol (vehicle). Animals were typically 10-12weeks of age and 100-150 g bodyweight at the start of the experiment.Treatment groups consisted of 5-8 animals. Non-anesthetized hamsterswere administered the test material onto the ventral surface of theright ear using a pipette at a volume of 20 μl per ear. Materials weregently massaged into the treatment site with a gloved finger forapproximately 15 sec. Hamsters received treatment once daily for 15-28consecutive days. Application of the test articles occurred within thesame 4-hour period on each application day. The left ear remaineduntreated and served as an internal control site. Animals were evaluateddaily for general appearance and potential clinical signs related totreatment such as edema, erythema, discoloration or other changes to theears. Hamsters were also assessed for general health by coat appearance,behavior, and activity level.

Sample Preparation for Histology.

Animals were euthanized by CO₂ asphyxiation approximately 16-20 hfollowing the final (21st) application. Tissue samples for sebaceousgland analysis were subsequently taken by histology personnel. The right(treated) and left (untreated) ears were carefully removed fromeuthanized hamsters. A 3.5 mm punch biopsy of the treated ear was markedwith a marking dye on the ventral surface. A punch biopsy of theuntreated ear was marked with a separate tissue-marking dye on theventral surface. Tissues were embedded in a labeled mold filled with“Neg 50” cryo-embedding medium and frozen on liquid nitrogen. Theseblocks were sequentially wrapped in Parafilm® then aluminum foil forstorage at −70° C. until required.

Sebaceous Gland Analysis.

To assess sebaceous gland status, ear cross-sections were initially cutat a thickness of approximately 8 μm onto glass slides and immediatelyfixed with 10% buffered formalin. Sections were stained with thelipid-specific Oil Red O dye by standard methods, covered with Faramount(Dakocytomation, Ca) acrylic mounting medium, cover slipped and thenallowed to set. A Tissue sections stained with Oil Red O were viewedwith a Spot RT digital camera mounted on an Olympus BX60 microscope.Tissue sections stained with Oil Red O were viewed with a Spot RTdigital camera mounted on an Olympus BX60 microscope. An image of thesection was taken using the 4× microscope objective. The image was savedusing the unique animal identification number, slide number, andmagnification. Relative sebaceous gland areas (red staining areas) weredetermined using Image-Pro software (Media Cybernetics Inc., SilverSpring, Md.). The area of image analysis was the dermis which includedthe region from the epidermal-dermal junction to the midline of thetissue demarcated by the central cartilage line. Data was expressed aspercentage of the area of the tissue cross section which was red incolor, representative of lipid-containing structures, in comparison tothe total area analyzed.

The following Biological Examples may be used by one skilled in the artto determine the effectiveness of the compounds of the invention intreating a human having a dermatological disorder or conditioncharacterized by sebaceous gland hyperactivity, in inhibiting sebaceousgland activity in a human, or in reducing T cell proliferation andcytokine secretion.

BIOLOGICAL EXAMPLE 1 Inhibition of Lipid Synthesis in SZ95 Sebocytes

The immortalized human sebocyte cell line, SZ95, was maintained inculture as described in Zouboulis, C. C. et al., J. Invest. Dermatol.(1999), Vol. 113, pp. 1011-1020. Lipid synthesis was stimulated bytreating SZ95 cells with arachidonic acid (AA). For measurement of lipidproduction and lipid inhibition studies, test compounds were dissolvedin dimethylsulfoxide (DMSO) and added at the desired concentration in96-well microtiter plates. The cells were then cultured for up to 72hours before the plates were washed 3 times with PBS and a final volumeof 200 μL PBS/well was added. To stain cell neutral lipids, 5 μL of NileRed solution (0.2 mg/mL dissolved in DMSO) was added to each well andincubated for a minimum of 60 minutes. Plate fluorescence was thenquantified using a fluorometric plate reader (excitation wavelength: 490nm; emission wavelength: 590 nm). Inhibition of lipid levels by the testcompound was expressed as the % reduction of the fluorescence ofAA-stimulated cells in the presence of the test compound relative to thevalues obtained for the unstimulated control cells. Cell viability wasmeasured by utilizing the conversion of a tetrazolium reagent (MTS) to acolored-formazan product by live cells. For these assays, the testcompound was dissolved in dimethylsulfoxide (DMSO) and added at thedesired concentration to cells seeded into 96-well plates. The cellswere cultured for 48 hours in the presence of the test compound beforethe plates were washed 3 times with PBS. A final volume of 100 μL ofculture medium per well was added. Twenty μL of MTS solution (0.2 mg/mLin sterile PBS) was added to each well and incubated for a minimum of 60minutes until the desired optical density was reached. The colordevelopment of the wells was measured using a plate reader at anabsorbance of 590 nm. Effect on cell viability by the test compound wasexpressed as the % reduction of the absorbance for AA-stimulated cellsin the presence of the test compound relative to the values obtained forthe untreated control cells.

Compounds of the invention, when tested in this assay, showed adose-dependent inhibition of lipid synthesis.

BIOLOGICAL EXAMPLE 2 Effect of a Compound of the Invention on LipidAccumulation by LNCaP Cells

The human prostate LNCaP adenocarcinoma cell line can be obtained fromAmerican Type Culture Collection. Cells are maintained in RPMI 1640medium containing 10% fetal calf serum (FCS), 4 mM Glutamax, 1 mM sodiumpyruvate, 1 mM HEPES, penicillin (100 U/mL) and streptomycin (100μg/mL). For experiments, approximately 10,000 cells/well are plated in6-well tissue culture plates in RPMI 1640 10% FBS for 72 hours. Tominimize potential serum androgen effects, medium containing 5%charcoal/dextran-stripped FCS is added for 72 hours. Lipid synthesis isthen stimulated by addition of the androgen dihydrotestosterone (DHT) at50 nM. A compound of the invention is solubilized in DMSO and added atvarious concentrations in RPMI 1640 containing 5%charcoal/dextran-treated. Cells are incubated in the presence of thesefactors for 96 hours at 37° C. Lipid accumulation is subsequentlyquantified by Nile Red staining and flow cytometric analysis. The lipidlevel of test compound-treated wells is compared to the result obtainedfor the vehicle-treated cells.

BIOLOGICAL EXAMPLE 3 Effect of Compounds of the Invention on 3T3-L1Adipocyte Differentiation and Lipid Accumulation

Mouse 3T3-L1 preadipocytes (American Type Culture Collection) arepassaged and maintained in Dulbecco's modified Eagles Medium (DMEM)supplemented with 10% fetal calf serum (FCS), 1 mM sodium pyruvate,penicillin (100 U/ml)/streptomycin (100 μg/ml) and 4 mM Glutamax(Gibco/Life Technologies). To initiate adipocyte differentiation, 3T3-L1cells are plated at confluency into culture plates or dishes and grownin supplemented DMEM for two days post-confluency. Initiation mediumconsists of DMEM with 0.5 mM 3-isobutyl-1-methylxanthine, 1 μMdexamethasone and human insulin at 10 μg/ml. Progression medium containsinsulin (10 μg/ml) which replaces the initiation medium after 48-72hours. Cellular lipid is imaged by Oil Red O staining.

BIOLOGICAL EXAMPLE 4 Effect of a Compound of the Invention onProliferation and Cytokine Production by Activated Human PeripheralBlood Mononuclear Cells (PBMC)

PBMC are isolated from different donors by density gradientcentrifugation. Different amounts of a compound of the invention areadded to PBMC cultures in the presence of two different stimuli sets.One activating stimulus is phytohemagglutinin (PHA), a plant-derivedmitogen that stimulates proliferation and cytokine synthesis by Tlymphocytes. These cell preparations are also activated using acombination of interferon-γ (IFN-γ) and lipopolysaccharide (LPS) tostimulate cytokine production by the monocyte fraction within PBMCpreparations. Following a 48 hour culture period, cell supernatants areobtained for simultaneous determination of cytokine levels using a flowcytometry-based quantification method. Cytokine levels are interpolatedfrom a standard curve generated in parallel. Cell viability is assessedusing a colorimetric assay based on the conversion of3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt (MTS) into a soluble formazan product by mitochondrialdehydrogenase of viable cells. Cell proliferation is determined byadding ³H-thymidine to the cultures and determining its level ofincorporation into DNA using scintillation counting.

BIOLOGICAL EXAMPLE 5 Determination of Solubility in Synthetic Sebum

Compounds described herein can be tested to evaluate their solubility inlipids. To determine the solubility, a synthetic sebum mixture was used.More specifically, approximately 5 mg of a compound was added into 1.5ml eppendorf tubes, which was then combined with 0.1 ml of syntheticsebum and then briefly vortexed. Mixtures were placed samples in ashaker pre-heated to 32° C. and then agitated overnight. Prior tosampling for HPLC analysis, tubes were placed in an eppendorf centrifugeand spun at 13000 rpm for 5 min to pellet the insoluble drug portion.Following centrifugation, 20 ul of the top portion of the solublefraction was sampled, in triplicate, into a 2 ml HPLC vial for analysisand the mass recorded. One ml of THF was then added to each vial tosolubilize sebum. To determine their concentrations, HPLC analysis ofall compounds was carried out under the same running conditions.

The following compounds of the invention were tested in this assay:

2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2-carboxylate (Compound A);

isopropyl 5-(tetradecyloxy)furan-2-carboxylate (Compound B)

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl5-(tetradecyloxy)furan-2-carboxylate (Compound C).

Table 1 shows that Compounds A, B and C exhibited considerably lowermeting points and far greater solubility in liquid synthetic sebum thanTOFA, which properties could promote their associations with the skinand delivery into the lipid-rich environment of the sebaceous glands.

TABLE 1 Molecular Melting Solubility in Liquid weight Point SyntheticSebum Compound (Daltons) (° C.) (mg/ml) TOFA 324.5 119  1.5 ± 0.4Compound A 406.5 37 28.9 ± 9.2 Compound B 366.5 <22 43.0 ± 0.5 CompoundC 436.5 35 13.6 ± 1.9

BIOLOGICAL EXAMPLE 6 In Vivo Assays

A series of hamster experiments were performed testing the potentialanti-sebaceous gland activity of compounds of the invention incomparison to TOFA. In all experiments, repeat topical applications ofTOFA and the compounds of the invention were well-tolerated. Neithererythema, edema, inflammation nor tissue necrosis was observed fortreated as well as untreated ears of these animals. Hamsters exhibitednormal behavior and weight gain through the duration of all experiments.

In these experiments, the compound of the invention, TOFA and vehiclewere applied onto male hamster ears. At the end of treatment, thehamsters were sacrificed and the area of sebaceous glands in the treatedarea was determined. The untreated ear in this test system acted as anassay internal control as well as a means to detect potential systemictreatment effects.

This hamster assay evaluated the effect of topical application of TOFAin parallel with three compounds of the invention (Compounds A, B and C)on hamster ear sebaceous glands. Test compounds were applied topicallydaily at 75 mM for 21 days in 40% DMA/30% acetone/30% ethanol.

As shown in FIG. 1, compounds of the invention (in particular, CompoundA), when tested in this assay, demonstrated the ability to reducesebaceous gland area when compared to TOFA and when compared to vehicle.

BIOLOGICAL EXAMPLE 7 In Vivo Assays—Sustained Inhibitory Effects

This example assessed hamster sebaceous gland size after 21 days ofapplication of Compound A as well as one and two weeks followingcessation of treatment. Compound A was applied in a mixture of 40%DMA/30% acetone/30% ethanol. One-week and two-week follow-up samplingtimes were included to assess sebaceous gland recovery characteristicsfollowing the treatment. A significant reduction in gland size was againproduced with 21 days of Compound A treatment (shown in FIG. 2). Incomparison to vehicle-treated animals, average gland area was 63.5%lower for hamsters treated with Compound A. For samples prepared twoweeks after completion of treatment, sebaceous gland counts for earsexposed to Compound A were significantly lower than control values. Thisfinding suggests a relatively sustained inhibitory effect on glandactivity following treatment of the TOFA analogs described herein.Moreover, the finding suggests that an exaggerated rebound effect maynot occur after cessation of a treatment regimen.

BIOLOGICAL EXAMPLE 8 In Vivo Assays—Reduced Sebaceous Gland

FIG. 3 shows the histological appearance of ear cross-sections preparedin a study in which animals were treated for 21 consecutive days withcontrol vehicle (40% DMA/30% acetone/30% ethanol), TOFA and Compound Aat a concentration of 75 mM in a mixture. No appreciable inflammatorycell presence evident for skin sections prepared from the ears ofhamsters treated with the control, TOFA and Compound A.

Sections were treated with Oil Red O to detect neutral lipids andcounter-stained with hematoxylin. Images are orientated with the ventralear surface positioned upwards. Reduced sebaceous gland area is evidentin the section prepared from a Compound A-treated hamster. In comparisonto vehicle-treated controls, epidermal thickness is greater for samplesobtained from hamsters treated with TOFA or Compound A.

Pharmaceutical Compositions of the Invention and Administration

Pharmaceutical compositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient are one aspect of the present invention. Thesepharmaceutical compositions may be in any form which allows for theactive ingredient, i.e., a compound of formula (I), to be administeredto a human in a therapeutically effective amount. For example, thepharmaceutical composition may be in the form of a semi-solid (gel),solid, liquid or gas (aerosol). Typical routes of administrationinclude, without limitation, systemic (including oral and parenteral),topical, buccal, transdermal, sublingual, nasal, rectal, vaginal, andintranasal administration. The term parenteral as used herein includessubcutaneous injections, needle-less injections, intravenous,intramuscular, epidural, intrasternal injection or infusion techniques.Pharmaceutical compositions of the invention are formulated so as toallow the active ingredients contained therein to be bioavailable uponadministration of the composition to a human. Pharmaceuticalcompositions of the invention that will be administered to a human maytake the form of one or more dosage units, where for example, a tablet,capsule, cachet or patch may be a single dosage unit, and a container ofa pharmaceutical composition of the invention in aerosol form may hold aplurality of dosage units.

In treating dermatological disorders characterized by sebaceous glandhyperactivity, the compound of formula (I) is preferably administered tothe skin (i.e., topically) of the human in need thereof indermatologically acceptable compositions, as described in more detailbelow. When such compositions are in use (e.g., when a dermatologicalcomposition comprising a compound of formula (I) and a dermatologicallyacceptable excipient is placed upon the skin of the human in needthereof), the compound of formula (I) is in continuous contact with theskin of the patient, thereby effecting treatment.

Any suitable amount of a compound of formula (I) can be employed in suchdermatological compositions, provided the amount employed effectivelyinhibits the production of sebum from sebocytes and remains stable inthe composition over a prolonged period of time. Preferably, thestability is over a prolonged period of time, e.g., up to about 3 years,up to 1 year, or up to about 6 months, which is typical in themanufacturing, packaging, shipping and/or storage of dermatologicallyacceptable compositions. A compound of formula (I) can be in solution,partially in solution with an undissolved portion or completelyundissolved suspension. A compound of formula (I) can be present in adermatological composition of the invention in a concentration rangefrom about 0.001 wt. % to about 80 wt. %, from about 0.001 wt. % toabout 50 wt. %, from about 0.001 wt. % to about 25 wt. %, or from about0.001 wt. % to about 6 wt. % of the dermatological composition. In oneembodiment, a compound of formula (I) can be present in a concentrationrange of from about 0.001 wt. % to about 10 wt. %, from about 0.1 wt. %to about 10 wt. % or from about 1.0 wt. % to about 5.0 wt. % of thedermatological composition. In another embodiment of the invention, adermatological formulation of a compound of formula (I) to beadministered topically contains (by weight) about 3% TOFA in about 40%dimethylacetamide (DMA)/30% acetone/30% ethanol.

A dermatological composition of the invention can be in the form of asolution, lotion, foam, gel, cream and/or ointment. Preferably, thedermatological composition will be a topical formulation, for example, agel, foam, cream or ointment.

A dermatological composition of the invention can contain one or more“lipophilic solvent(s)” that acts as a carrier into the pilosebaceousunit. A lipophilic solvent useful in the invention can be miscible withwater and/or lower chain alcohols and have a vapor pressure less thanwater at 25° C. (˜23.8 mm Hg). A lipophilic solvent useful in theinvention can be a glycol, specifically propylene glycol. In particular,the propylene glycol can be from the class of polyethylene glycols,specifically polyethylene glycols ranging in molecular weight from 200to 20000. Preferably, the solvent would be part of a class of glycolethers. More specifically, a lipophilic solvent of the invention wouldbe diethylene glycol monoethyl ether (transcutol). As used herein,“diethylene glycol monoethyl ether” (“DGME”) or “transcutol” refers to2-(2-ethoxyethoxy)ethanol {CAS NO 001893} or ethyoxydiglycol.

A dermatological composition of the invention can also contain one ormore “filler(s)” that has a vapor pressure greater than or equal to 23.8mm Hg at 25° C. The filler should have a vapor pressure greater than orequal to the lipophilic solvent as to concentrate the compound offormula (I) on the skin. Preferred concentration range of a singlefiller or the total of a combination of fillers can be from about 0.1wt. % to about 10 wt. %, more preferably from about 10 wt. % to about 50wt. %, more specifically from about 50 wt. % to about 95 wt. % of thedermatological composition. Non-limiting examples for use herein includewater and lower alcohols, including ethanol, 2-propanol and n-propanol.More preferably, the filler is water, ethanol and/or 2-propanol.Specifically, the filler would be ethanol and/or water.

A dermatological composition of the invention can also contain one ormore “humectant(s)” used to provide a moistening effect. Preferably thehumectant remains stable in the composition. Any suitable concentrationof a single humectant or a combination of humectants can be employed,provided that the resulting concentration provides the desiredmoistening effect. Typically, the suitable amount of humectant willdepend upon the specific humectant or humectants employed. Preferredconcentration range of a single humectant or the total of a combinationof humectants can be from about 0.1 wt. % to about 70 wt. %, morepreferably from about 5.0 wt. % to about 30 wt. %, more specificallyfrom about 10 wt. % to about 25 wt. % of the dermatological composition.Non-limiting examples for use herein include glycerin, polyhydricalcohols and silicone oils. More preferably, the humectant is glycerin,propylene glycol and/or cyclomethicone. Specifically, the filler wouldbe glycerine and/or cyclomethicone.

A dermatological composition of the invention can also contain a gellingagent that increases the viscosity of the final solution. The gellingagent can also act as an emulsifying agent. The present dermatogologicalcompositions can form clear gels and soft gels, which upon applicationto the skin can break down and deteriorate, affording gels that do notdry on the skin. Typically, the concentration and combination of gellingagents will depend on the physical stability of the finished product.Preferred concentration range of a gelling agent can be from about 0.01wt. % to about 20 wt. %, more preferably from about 0.1 wt. % to about10 wt. %, more specifically from about 0.5 wt. % to about 5 wt. % of thedermatological composition. Non-limiting examples for use herein includeclasses of celluloses, acrylate polymers and acrylate crosspolymers.Preferably, hydroxypropyl cellulose, hydroxymethyl cellulose, PluronicPF127 polymer, carbomer 980, carbomer 1342 and carbomer 940, morepreferably hydroxypropyl cellulose, Pluronic PF127 carbomer 980 andcarbomer 1342, more specifically hydroxypropyl cellulose (Klucel® EF, GFand/or HF), Pluronic PF127, carbomer 980 and/or carbomer 1342 (Pemulen®TR-1, TR-2 and/or Carbopol® ETD 2020).

A dermatological composition of the invention can contain one or moreanti-oxidants, radical scavengers, and/or stabilizing agents, preferredconcentration range from about 0.001 wt. % to about 0.1 wt. %, morepreferably from about 0.1 wt. % to about 5 wt. % of the dermatologicalcomposition. Non-limiting examples for use herein includebutylatedhydroxytoluene, butylatedhydroxyanisole, ascorbyl palmitate,citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbicacid, tocophersolan and propyl gallate. More specifically theanti-oxidant can be ascorbyl palmitate, vitamin E acetate, vitaminE-TPGS, vitamin E or butylatedhydroxytoluene.

A dermatological composition of the invention can also containpreservatives that exhibit anti-bacterial and/or anti-fungal properties.Preservatives can be present in a gelled dermatological composition ofthe invention to minimize bacterial and/or fungal over its shelf-life.Preferred concentration range of preservatives in a dermatologicalcomposition of the invention can be from about 0.001 wt. % to about 0.01wt. %, more preferably from about 0.01 wt. % to about 0.5 wt. % of thedermatological composition. Non-limiting examples for use herein includediazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, andethylparaben. More specifically the preservative would be a combinationof methylparaben and propylparaben.

A dermatological composition can optionally include one or morechelating agents. As used herein, the term “chelating agent” or“chelator” refers to those skin benefit agents capable of removing ametal ion from a system by forming a complex so that the metal ioncannot readily participate in or catalyze chemical reactions. Thechelating agents for use herein are preferably formulated atconcentrations ranging from about 0.001 wt. % to about 10 wt. %, morepreferably from about 0.05 wt. % to about 5.0 wt. % of thedermatological composition. Non-limiting examples for use herein includeEDTA, disodium edeate, dipotassium edeate, cyclodextrin, trisodiumedetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acidand potassium gluconate. Specifically, the chelating agent can be EDTA,disodium edeate, dipotassium edate, trisodium edetate or potassiumgluconate.

The dermatological compositions of this invention can be provided in anycosmetically suitable form, preferably as a lotion or a cream, but alsoin an ointment or oil base, as well as a sprayable liquid form (e.g., aspray that includes TOFA in a base, vehicle or carrier that dries in acosmetically acceptable way without the greasy appearance that a lotionor ointment would have when applied to the skin).

In addition, the dermatological compositions of the invention caninclude one or more compatible cosmetically acceptable adjuvantscommonly used, such as colorants, fragrances, emollients, humectants andthe like, as well as botanicals, such as aloe, chamomile and the like.

In topically administering the dermatological compositions of theinvention, the skin of the human to be treated can be optionallypre-treated (such as washing the skin with soap and water or cleansingthe skin with an alcohol-based cleanser) prior to administration of thedermatological composition of the invention.

In treating dermatological disorders or conditions characterized bysebaceous gland hyperactivity, a compound of formula (I) or apharmaceutical composition comprising a compound of formula (I) can alsobe administered systemically, preferably orally, to the human in needthereof in pharmaceutically acceptable compositions, as described inmore detail below.

A pharmaceutical composition of the invention to be orally administeredcan be prepared by combining a compound of formula (I) with anappropriate pharmaceutically acceptable carrier, diluent or excipient bystandard methods known to one skilled in the art. Pharmaceuticalcompositions of the invention are formulated so as to allow the compoundof formula (I) contained therein to be bioavailable upon administrationof the composition to a human.

A pharmaceutical composition of the invention to be orally administeredmay be formulated into a powder, granule, compressed tablet, pill,capsule, chewing gum, wafer or the like form. Such a solid compositionwill typically contain one or more inert diluents or edible carriers. Inaddition, one or more of the following may be present: binders such ascarboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gumtragacanth or gelatin; excipients such as starch, lactose or dextrins,disintegrating agents such as alginic acid, sodium alginate, Primogel,corn starch and the like; lubricants such as magnesium stearate orSterotex; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; a flavoring agent such as peppermint,methyl salicylate or orange flavoring; and a coloring agent.

When a pharmaceutical composition of the invention is in the form of acapsule, for example, a gelatin capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as polyethyleneglycol or oil.

A pharmaceutical composition of the invention to be orally administeredmay also be in the form of a liquid, for example, an elixir, syrup,solution, emulsion or suspension. The pharmaceutical composition mayalso optionally contain one or more of a sweetening agent,preservatives, dye/colorant and flavor enhancer.

Liquid pharmaceutical compositions of the invention may also include oneor more of the following adjuvants: sterile water, saline solution(preferably physiological saline solution), Ringer's solution, isotonicsodium chloride, fixed oils such as synthetic mono or diglycerides whichmay serve as the solvent or suspending medium, polyethylene glycols,glycerin, propylene glycol or other solvents; antibacterial agents suchas benzyl alcohol or methyl paraben; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose.

A liquid pharmaceutical composition of the invention contains atherapeutically effective amount of a compound of formula (I) whenadministered to a human in need thereof. Typically, this amount is atleast 0.01% of a compound of formula (I) in the composition. This amountmay be varied to be between about 0.1 wt. % and about 70% of the totalweight of the composition. Preferred oral pharmaceutical compositionscontain a compound of formula (I) at a concentration range of betweenabout 1.0 wt. % and about 50 wt. % of the oral composition.

A pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredient. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredient may be encased in a gelatincapsule.

A pharmaceutical composition of the invention in solid or liquid formmay also include an agent that binds to a compound of formula (I) andthereby assists in the systemic delivery of the compound of formula (I).Suitable agents that may act in this capacity include a monoclonal orpolyclonal antibody, a protein or a liposome.

Systemic administration of the pharmaceutical compositions of theinvention also include administration by injection, e.g., subcutaneous,intravenous, intramuscular, intrathecal or intraperitoneal injection, aswell as transdermal, transmucosal, or pulmonary administration andneedle-less injection administration.

Useful injectable pharmaceutical compositions include sterilesuspensions, solutions or emulsions of the active compound(s) in aqueousor oily vehicles. The compositions may also contain formulating agents,such as suspending, stabilizing and/or dispersing agent. Thepharmaceutical compositions for injection may be presented in unitdosage form, e.g., in ampules or in multidose containers, and maycontain added preservatives.

Alternatively, the injectable pharmaceutical compositions may beprovided in powder form for reconstitution with a suitable vehicle,including but not limited to sterile pyrogen free water, buffer,dextrose solution, etc., before use. To this end, the active compound,i.e., a compound of formula (I), may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For prolonged delivery, a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be formulated as a depot preparation foradministration by implantation or intramuscular injection. A compound offormula (I), or a pharmaceutically acceptable salt thereof, may beformulated with suitable polymeric or hydrophobic materials (e.g., as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, for percutaneous absorption may be used. Tothis end, permeation or penetration enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S.Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189;U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No.5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Administration of the pharmaceutical compositions of the invention byneedle-less injection can be employed using the techniques disclosed inU.S. Pat. No. 6,756,053.

Alternatively, other pharmaceutical delivery systems may be employed forthe pharmaceutical compositions of the invention. Liposomes andemulsions are well-known examples of delivery vehicles that may be usedto deliver active compound(s) or prodrug(s). Certain organic solventssuch as dimethylsulfoxide (DMSO) may also be employed, although usuallyat the cost of greater toxicity.

The pharmaceutical compositions of the invention may, if desired, bepresented in a pack or dispenser device which may contain one or moreunit dosage forms containing the active compound(s). The pack may, forexample, comprise metal or plastic foil, such as a blister pack. Thepack or dispenser device may be accompanied by instructions foradministration.

The pharmaceutical compositions of the invention as set forth above maybe prepared by methodology well known in the pharmaceutical art or bythe method described herein. See, for example, Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990).

The pharmaceutical compositions of the invention are administered to ahuman in a therapeutically effective amount, which will vary dependingupon a variety of factors including the activity of the compound offormula (I); the metabolic stability and length of action of thecompound of formula (I); the age, body weight, general health, sex, anddiet of the human; the mode and time of administration; the rate ofexcretion; the drug combination; and the severity of the particulardisorder or condition. Generally, a therapeutically effective daily doseof a compound of formula (I) is (for a 70 kg mammal) from about 0.001mg/kg (i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 gm); preferably atherapeutically effective dose is (for a 70 kg mammal) from about 0.01mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 gm); more preferably atherapeutically effective dose is (for a 70 kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

The following Formulation Examples 1-5 provide dermatologicalcompositions of the invention comprising a representative compound offormula (I) and one or more dermatologically acceptable excipients.

FORMULATION EXAMPLE 1 Dermatological Alcoholic Gel Formulation

The product of the following formulation is a semi-solid clear gel.

Percent Ingredient w/w Compound of formula (I) 1.0 Diethylene GlycolMonoethyl Ether, NF 32.0 Tocophersolan, NF 1.0 Hydroxypropyl Cellulose,NF (Klucel ® GF) 4.0 Edetate Disodium 0.05 Alcohol, Dehydrated, NF 61.95

The above formulation may be prepared as follows. The alcohol anddiethylene glycol monoethyl ether are combined. Tocophersolan, edetatedisodium and the compound of formula (I) are dissolved with mixing.Hydroxypropyl cellulose is added and quickly and evenly dispersed withhigh-speed mixing. The product is removed from mixing after uniformdispersion.

FORMULATION EXAMPLE 2 Dermatological Aqueous Gel Formulation

The product of the following formulation is a semi-solid clear soft gel.

Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene GlycolMonoethyl 30.0 Ether, NF Glycerin, USP 5.0 Tocophersolan, NF 1.0Methylparaben, NF 0.1 Propylparaben, NF 0.02 Edetate Disodium 0.05Acrylates/C10-C30 Alkyl 2.0 Acrylate Crosspolymer, NF Polysorbate 80, NF0.1 Trolamine, NF to pH 6.75 Water, USP to 100.0

The above formulation may be prepared as follows. The liquids,diethylene glycol monoethyl ether, glycerin and water, are mixed.Polysorbate 80 and tocophersolan are added and mixed to dissolve. Thecompound of formula (I) is added and mixed to dissolve. Edetatedisodium, methylparaben, and propylparaben are added and mixed todissolve. Acrylates/C10-C30 alkyl acrylate crosspolymer are quicklydispersed with high-speed mixing until uniform mixture obtained.Trolamine is added with constant mixing to obtain a viscous gel at a pHof approximately 6.75 (when diluted 1:9 with water).

FORMULATION EXAMPLE 3 Dermatological Hydroalcoholic Gel Formulation

The product of the following formulation is a semi-solid clear soft gel.

Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene GlycolMonoethyl 30.0 Ether, NF Alcohol, NF 25.0 Glycerin, USP 5.0Tocophersolan, NF 1.0 Methylparaben, NF 0.1 Propylparaben, NF 0.02Edetate Disodium 0.05 Hydroxypropyl Cellulose, NF 2.0 (Klucel ® EF)Acrylates/C10-C30 Alkyl 1.0 Acrylate Crosspolymer, NF Polysorbate 80, NF0.05 Trolamine, NF to pH 6.75 Water, USP to 100.0

The above formulation may be prepared as follows. The liquids,diethylene glycol monoethyl ether, glycerin alcohol and water, aremixed. Polysorbate 80 and tocophersolan are added and mixed to dissolve.The compound of formula (I) is added and mixed to dissolve. Edetatedisodium, methylparaben and propylparaben are added and mixed todissolve. Acrylates/C10-C30 alkyl acrylate crosspolymer andhydroxypropyl cellulose are quickly dispersed with high-speed mixinguntil uniform mixture obtained. Trolamine is added with constant mixingto obtain a viscous gel at a pH of approximately 6.75 (when diluted 1:9with water).

FORMULATION EXAMPLE 4 Dermatological Cream Formulation

A compound of formula (I) may also be formulated as a cream, an exampleof which is as follows:

Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene GlycolMonoethyl 20.0 Ether, NF White Petrolatum 5.0 Isopropyl Myristate 5.0Cetostearyl Alcohol 5.0 Trilaureth-4 Phosphate 1.0 Tocophersolan, NF 1.0Cyclomethicone, NF 5.0 Methylparaben, NF 0.2 Propylparaben, NF 0.04Edetate Disodium 0.05 Carbomer 940 0.15 Acrylates/C10-C30 Alkyl 0.15Acrylate Crosspolymer, NF Trolamine, NF to pH 6.75 Water, USP to 100.0

The above formulation may be prepared as follows:

A. Water Phase

Water and diethylene glycol monoethyl ether are mixed together.Tocophersolan is added and mixed to dissolve. The compound of formula(I) is added and mixed to dissolve. Trilaureth-4 phosphate, edetatedisodium, methylparaben and propylparaben are added and mixed todissolve. Acrylates/C10-C30 alkyl acrylate crosspolymer and carbomer 940are quickly dispersed with high-speed mixing until uniform mixtureobtained. The resulting mixture is heated, while stirring, at atemperature of between about 65° C. and about 75° C. to form a solution.

B. Oil Phase

White petrolatum, cyclomethicone, isopropyl myristate and cetostearylalcohol are combined in a separate vessel and melted completely at atemperature of between about 65° C. and about 75° C. and stirred.

C. While stirring the water phase, the oil phase is slowly added until auniform emulsion is obtained. Trolamine is slowly added to the resultingemulsion to obtain a cream at a pH of approximately 6.75. The product iscooled to 25° C. with continuous mixing.

FORMULATION EXAMPLE 5 Dermatological Foam Formulation

A compound of formula (I) may also be formulated as a foam, an exampleof which is as follows:

Ingredient Percent w/w* Compound of formula (I) 1.0 Diethylene GlycolMonoethyl 25.0 Ether, NF Stearyl Alcohol, NF 8.0 Laureth-23 0.5 PEG-100Stearate 1.0 Tocophersolan, NF 1.0 Propylparaben, NF 0.3 EdetateDisodium 0.05 Acrylates/C10-C30 Alkyl 0.2 Acrylate Crosspolymer, NFTrolamine, NF to pH 6.75 Water, USP to 100.0 *Propellant is 4.0 wt. % offinal formulation. The propellant is a single gas or a mixture of gases.Suitable gases include butane, isobutane, propane, isopropane andisopentate.

The above formulation may be prepared as follows:

A. Water Phase

Water and diethylene glycol monoethyl ether are mixed. Tocophersolan isadded and mixed to dissolve. TOFA is added and mixed to dissolve.Edetate disodium and propylparaben are added and mixed to dissolve.Acrylates/C10-C30 alkyl acrylate crosspolymer is quickly dispersed withhigh-speed mixing until uniform mixture obtained. The resulting mixtureis heated, while stirring, to solution at a temperature of between about60° C. and about 70° C.

B. Oil Phase

Stearyl alcohol, laureth-23 and PEG-100 stearate are combined in aseparate vessel and melted completely, while stirring, at a temperatureof between about 60° C. and about 70° C.

C. While stirring the water phase, the oil phase is added until auniform emulsion is obtained. Trolamine is added to afford the desiredpH. The resulting formulation is cooled to 25° C. with continuousmixing. The formulation is packaged in an appropriate air-tightcontainer under pressure with propellant.

Combination Therapy

Compounds of the invention may be usefully combined with one or moreother therapeutic agents in the treatment of dermatological disorders orconditions characterized by sebaceous gland hyperactivity. For example,a compound of the invention may be administered simultaneously,sequentially or separately in combination with other therapeutic agents,including, but not limited to:

-   -   topical/oral antibiotics, e.g., clindamycin, tetracycline,        minoccline, deoxycycline, erythromycin, trimethoprim, and        azithromycin;    -   retinoids, e.g., Accutane®, tretinion, tazarotene, and        adapalene;    -   benzoyl peroxide;    -   blue/red light;    -   photodynamic therapy (PDT);    -   Anti-androgenic compounds, e.g., PSK 3841;    -   5-alpha reductase type I inhibitors;    -   comedolytics, e.g., salicylic acid, azelaic acid, sulfur and        resorcinol.

As used herein “combination” refers to any mixture or permutation of acompound of the invention and one or more additional therapeutic agentsuseful in the treatment of dermatological disorders or conditions.Unless the context makes clear otherwise, “combination” may includesimultaneous or sequentially delivery of a compound of the inventionwith one or more therapeutic agents. Unless the context makes clearotherwise, “combination” may include dosage forms of a compound of theinvention (e.g., dermatological or pharmaceutical compositionscomprising a compound of the invention and a dermatological acceptableexcipient) with another therapeutic agent. Unless the context makesclear otherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include compositionscomprising a compound of the invention and another therapeutic agent.Dosage forms, routes of administration and dermatological andpharmaceutical compositions include, but are not limited to, thosedescribed herein.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A compound of formula (I):

wherein: R¹ is —O—R², —O—R³—OR², —O—R³—OC(O)—N(R⁵)R⁶, —O—R³—N(R⁵)R⁶,—O—R³—N(R⁴)C(O)OR⁵, —O—R³—C(O)OR⁵, —O—R³—C(O)N(R⁵)R⁶ or —N(R⁵)S(O)₂—R⁴;each R² is independently alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; each R³ isindependently an optionally substituted alkylene chain; and R⁴ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; each R⁵ is independently hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and each R⁶ is alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl or —R³—C(O)OR⁴;or any R⁵ and R⁶, together with the nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl; as a single stereoisomer or as a mixturethereof; or a pharmaceutically acceptable salt thereof.
 2. The compoundof claim 1 wherein: R¹ is —O—R²; and R² is independently alkyl orheterocyclylalkyl.
 3. The compound of claim 2 selected from: isopropyl5-(tetradecyloxy)furan-2-carboxylate; 4-methylpentyl5-(tetradecyloxy)furan-2-carboxylate; and(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl5-(tetradecyloxy)furan-2-carboxylate.
 4. The compound of claim 1wherein: R¹ is —O—R²; and R² is haloalkyl or substituted aryl.
 5. Thecompound of claim 4 selected from: 2,2,2-trifluoroethyl5-(tetradecyloxy)furan-2-carboxylate; 2,2,2-trichloroethyl5-(tetradecyloxy)furan-2-carboxylate; 2-bromoethyl5-(tetradecyloxy)furan-2-carboxylate; and2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid.
 6. The compound ofclaim 1 wherein: R¹ is —O—R³—OR²; R² is optionally substitutedheterocyclylalkyl; and R³ is an optionally substituted alkylene chain.7. The compound of claim 6 which is3-(tetrahydro-2H-pyran-2-yloxy)propyl5-(tetradecyloxy)furan-2-carboxylate.
 8. The compound of claim 1wherein: R¹ is —O—R³—OC(O)—N(R⁵)R⁶; each R² is independently alkyl,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted substituted heteroarylalkyl; R³ is an optionally substitutedalkylene chain; and R⁵ is hydrogen, alkyl, optionally substitutedcycloalkyl, optionally substituted aryl or optionally substitutedaralkyl; and R⁶ is alkyl, optionally substituted cycloalkyl, optionallysubstituted aralkyl or —R³—C(O)OR³; and or any R⁵ and R⁶, together withthe nitrogen to which they are both attached, form an optionallysubstituted N-heterocyclyl or an optionally substituted N-heteroaryl. 9.The compound of claim 8 selected from:1-(benzyl(methyl)carbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate;1-((2-ethoxy-2-oxoethyl)(methyl)carbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate; 4 (2S)-2-benzyl1-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)pyrrolidine-1,2-dicarboxylate;1-(4-phenylcyclohexanecarbonyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate;1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl3-phenylpyrrolidine-1-carboxylate;1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl3,4-dihydroisoquinoline-2(1H)-carboxylate;1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl piperidine-1-carboxylate;1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl morpholine-4-carboxylate;1-tert-butyl4-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)piperazine-1,4-dicarboxylate;and 1-(dicyclohexylcarbamoyloxy)ethyl5-(tetradecyloxy)furan-2-carboxylate.
 10. The compound of claim 1wherein: R¹ is —O—R³—N(R⁵)R⁶; R³ is an optionally substituted alkylenechain; and R⁵ is hydrogen, alkyl, optionally substituted cycloalkyl,optionally substituted aryl or optionally substituted aralkyl; and R⁶ isalkyl, optionally substituted cycloalkyl, optionally substituted aralkylor —R³—C(O)OR⁴; and or any R⁵ and R⁶, together with the nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.
 11. Thecompound of claim 10 selected from: 2-(dimethylamino)ethyl5-(tetradecyloxy)furan-2-carboxylate; 2-morpholinoethyl5-(tetradecyloxy)furan-2-carboxylate; or 3-morpholinopropyl5-(tetradecyloxy)furan-2-carboxylate.
 12. The compound of claim 1wherein: R¹ is —O—R³—N(R⁴)C(O)OR⁵ R³ is an optionally substitutedalkylene chain; and R⁴ is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; and R⁵ ishydrogen, alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl or optionally substituted aralkyl.
 13. The compound ofclaim 1 wherein: R¹ is —O—R³—C(O)OR⁵ R³ is an optionally substitutedalkylene chain; and R⁵ is hydrogen, alkyl, optionally substitutedcycloalkyl, optionally substituted aryl or optionally substitutedaralkyl.
 14. The compound of claim 1 wherein: R¹ is —O—R³—C(O)N(R⁵)R⁶;R³ is an optionally substituted alkylene chain; and R⁵ is hydrogen,alkyl, optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and R⁶ is alkyl, optionally substitutedcycloalkyl, optionally substituted aralkyl or —R³—C(O)OR⁴; or R⁵ and R⁶,together with the nitrogen to which they are both attached, form anoptionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl.
 15. The compound of claim 14 selected from:2-(benzyl(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate;tert-butyl4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine-1-carboxylate;2-(dicyclohexylamino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate;2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate;2-oxo-2-(4-phenylpiperzin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate;2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl5-tetradecyloxy)furan-2-carboxylate;2-oxo-2-(piperidin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylate;2-morpholino-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate;2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl5-(tetradecyloxy)furan-2-carboxylate; and (S)-benzyl1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidine-2-carboxylate.16. The compound of claim 1 wherein: R¹ is —N(R⁵)S(O)₂—R⁴; R⁴ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; and R⁵ is independently hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl.
 17. The compound of claim 16 which is5-(tetradecyloxy)-N-tosylfuran-2-carboxamide. 18.-25. (canceled)
 26. Apharmaceutical composition comprising: a therapeutically effectiveamount of a compound of formula (I):

wherein: R¹ is —O—R², —O—R³—OR², —O—R³—OC(O)—N(R⁵)R⁶, —O—R³—N(R⁵)R⁶,—O—R³—N(R⁴)C(O)OR⁵, —O—R³—C(O)OR⁵, —O—R³—C(O)N(R⁵)R⁶ or —N(R⁵)S(O)₂—R⁴;each R² is independently alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; each R³ isindependently an optionally substituted alkylene chain; and R⁴ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; each R⁵ is independently hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and each R⁶ is alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl or —R³—C(O)OR⁴;or any R⁵ and R⁶, together with the nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl; as a single stereoisomer or as a mixturethereof, or a pharmaceutically acceptable salt thereof; and apharmaceutically or dermatologically acceptable excipient. 27.-34.(canceled)
 35. A method for treating a human having a dermatologicaldisorder or condition comprising: administering to the human atherapeutically effective amount of a compound of formula (I):

wherein: R¹ is —O—R², —O—R³—OR², —O—R³—OC(O)—N(R⁵)R⁶, —O—R³—N(R⁵)R⁶,—O—R³—N(R⁴)C(O)OR⁵, —O—R³—C(O)OR⁵, —O—R³—C(O)N(R⁵)R⁶ or —N(R⁵)S(O)₂—R⁴;each R² is independently alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; each R³ isindependently an optionally substituted alkylene chain; and R⁴ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; each R⁵ is independently hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and each R⁶ is alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl or —R³—C(O)OR⁴;or any R⁵ and R⁶, together with the nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl; as a single stereoisomer or as a mixturethereof; or as a pharmaceutically acceptable salt, or as a part of apharmaceutical composition, and wherein the dermatological disorder orcondition is characterized by sebaceous gland hyperactivity.
 36. Themethod of claim 35 wherein the dermatological disorder or condition isacne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-typerosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia,Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, oroily skin.
 37. The method of claim 36 wherein the dermatologicaldisorder is acne.
 38. The method of claim 36 wherein the dermatologicalcondition is oily skin.
 39. A method for inhibiting sebaceous glandactivity in a human comprising: administering to the human atherapeutically effective amount of a compound of formula (I):

wherein: R¹ is —O—R², —O—R³—OR², —O—R³—OC(O)—N(R⁵)R⁶, —O—R³—N(R⁵)R⁶,—O—R³—N(R⁴)C(O)OR⁵, —O—R³—C(O)OR⁵, —O—R³—C(O)N(R⁵)R⁶ or —N(R⁵)S(O)₂—R⁴;each R² is independently alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; each R³ isindependently an optionally substituted alkylene chain; and R⁴ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; each R⁵ is independently hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and each R⁶ is alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl or —R³—C(O)OR⁴;or any R⁵ and R⁶, together with the nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl; as a single stereoisomer or as a mixturethereof; or as a pharmaceutically acceptable salt, or as a part of apharmaceutical composition.
 40. A method for treating a human having adisorder or condition characterized by inflammation comprising:administering to the human a therapeutically effective amount of acompound of formula (I):

wherein: R¹ is —O—R², —O—R³—OR², —O—R³—OC(O)—N(R⁵)R⁶, —O—R³—N(R⁵)R⁶,—O—R³—N(R⁴)C(O)OR⁵, —O—R³—C(O)OR⁵, —O—R³—C(O)N(R⁵)R⁶ or —N(R⁵)S(O)₂—R⁴;each R² is independently alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; each R³ isindependently an optionally substituted alkylene chain; and R⁴ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; each R⁵ is independently hydrogen, alkyl,optionally substituted cycloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and each R⁶ is alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl or —R³—C(O)OR⁴;or any R⁵ and R⁶, together with the nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl; as a single stereoisomer or as a mixturethereof; or as a pharmaceutically acceptable salt, or as a part of apharmaceutical composition.
 41. The method of claim 40 wherein thedisorder or condition is inflammatory acne.
 42. The method of claim 40wherein treating the human having a disorder or condition characterizedby inflammation comprises reducing T cell proliferation and cytokinesecretion in the human.